Heterocyclic compound

ABSTRACT

Provided is a heterocyclic compound having a superior RBP4-lowering action and useful as a medicament for the prophylaxis or treatment of a disease or symptom mediated by an increase in RBP4 or retinol supplied by RBP4. A compound represented by the formula (I): 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as defined in the Description, or a salt thereof has a superior RBP4-lowering action, and is useful as a medicament for the prophylaxis or treatment of a disease or symptom mediated by an increase in RBP4 or retinol supplied by RBP4.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound useful as amedicament for the prophylaxis or treatment of a disease or conditionmediated by an increase in RBP4 or retinol supplied by RBP4 such asage-related macular degeneration, Stargardt's disease and the like.

BACKGROUND OF THE INVENTION

It is known that retinol binding protein 4 (hereinafter sometimes to beabbreviated as “RBP4”) is a sole blood retinol transfer protein mainlyproduced in the liver.

RBP4 forms a complex by binding to retinol and TTR (transthyretin) andis stably present in blood. When RBP4 is dissociated from TTR andbecomes free, it is decomposed in and excreted from the kidneycomparatively rapidly. It is unknown whether the binding of RBP4 andretinol is indeed essential for the formation of a complex with TTR.However, fenretinide, a retinol derivative, inhibits binding of RBP4 andretinol, and consequently inhibits formation of a complex with TTR. Itis known that administration of fenretinide to an animal induceslowering of blood RBP4 (non-patent document 1).

The relationship between retinol supplied by RBP4 and ophthalmicdiseases has been reported. For example, an excessive vitamin A level inthe eye can induce various retina diseases including maculardegeneration, and a decrease in RBP4 is effective for the prophylaxis ortreatment of these ophthalmic diseases (patent document 1).

Fenretinide has been investigated in patients affected with geographicatrophy (GA), which is the most progressed form of atrophic age-relatedmacular degeneration (AMD). Fenretinide has been suggested todiscontinue accumulation of retinol (vitamin A) toxin via affinity toRBP4. It is assumed to delay formation and accumulation of toxicityby-products, for example, A2E (bis-retinoid pyridinium) considered to beinvolved in the loss of eyesight in diseases such as GA and the like.Sirion Therapeutics, Inc. publicly reported affirmative results of theanalysis of phase two tests for evaluating fenretinide for the treatmentof GA related to AMD.

From the above, application of a medicament having an action to decreaseblood RBP4 value (concentration) to the prophylaxis or treatment ofophthalmic diseases is expected. In the present specification, the“action to decrease blood RBP4 value (concentration)” is sometimesreferred to as an “RBP4-lowering action”, and the “medicament having anaction to decrease blood RBP4 value (concentration)” is sometimesreferred to as an “RBP4-lowering drug”.

Patent document 2 discloses the following compound having aRBP4-lowering action, and useful for the prophylaxis or treatment ofdiabetes, obesity and the like.

wherein each symbol is as defined in the document.

Patent document 3 discloses the following compound having aRBP4-lowering action, and useful for the prophylaxis or treatment ofdiabetes and the like.

wherein each symbol is as defined in the document.

Patent document 4 discloses the following compound having aRBP4-lowering action, and useful for the prophylaxis or treatment ofdiabetes, age-related macular degeneration and the like.

wherein each symbol is as defined in the document.

DOCUMENT LIST Patent Documents

-   patent document 1: WO 2009/042444-   patent document 2: WO 2009/051244-   patent document 3: WO 2009/145286-   patent document 4: WO 2010/119992

Non-Patent Document

-   non-patent document 1: Biochim. Biophys. Acta, 1294, 48-54 (1996)

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a heterocyclic compoundhaving a RBP4-lowering action and useful for the prophylaxis ortreatment of a disease or condition mediated by an increase in RBP4 orretinol supplied by RBP4 such as age-related macular degeneration,Stargardt's disease and the like, and a medicament containing same.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the above-mentioned problems and found that a compound representedby the following formula (I) has a superior RBP4-lowering action, whichresulted in the completion of the present invention.

Therefore, the present invention provides the following.

[1] A compound represented by the formula (I):

wherein

ring A is an optionally further substituted benzene ring;

R is a hydrogen atom or a C₁₋₆ alkyl group;

R¹ is a C₃₋₆ cycloalkyl group optionally substituted by substituent(s)selected from a fluorine atom and an optionally substituted alkyl group;

ring B is an optionally further substituted pyrrolidine ring; and

R² and R³ are each independently a hydrogen atom or a substituent, or R²and R³ are optionally joined to form an optionally substituted ring,

or a salt thereof (sometimes to be abbreviated as “compound (I)” in thepresent specification);[2] the compound of the above-mentioned [1], wherein R is a hydrogenatom, or a salt thereof;[3] the compound of [1] or [2], wherein ring A is a benzene ringoptionally further substituted by a substituent selected from a halogenatom and a C₁₋₆ alkyl group, or a salt thereof;[4] the compound of [1] or [2], wherein R¹ is a C₃₋₆ cycloalkyl groupoptionally substituted by substituent(s) selected from a C₁₋₆ alkylgroup optionally substituted by a fluorine atom, or a salt thereof;[5] the compound of [1] or [2], wherein ring B is a pyrrolidine ringoptionally further substituted by a substituent selected from a fluorineatom and a C₁₋₆ alkyl group, or a salt thereof;[6] the compound of [1] or [2], wherein R² and R³ are each independentlya hydrogen atom, a halogen atom, or a C₁₋₆ alkyl group, or R² and R³ areoptionally joined to form a C₃₋₄ cycloalkane ring, or a salt thereof;[7] the compound of [1] or [2], wherein ring A is a benzene ringoptionally further substituted by a substituent selected from a halogenatom and a C₁₋₆ alkyl group;

R¹ is a C₃₋₆ cycloalkyl group optionally substituted by substituent(s)selected from a C₁₋₆ alkyl group optionally substituted by a fluorineatom;

ring B is a pyrrolidine ring optionally further substituted by asubstituent selected from a fluorine atom and a C₁₋₆ alkyl group;

R² and R³ are each independently a hydrogen atom, a halogen atom, or aC₁₋₆ alkyl group, or R² and R³ are optionally joined to form a C₃₋₄cycloalkane ring, or a salt thereof;

[8]3-((3S)-3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid or a salt thereof;[9] 3-(3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid or a salt thereof;[10]3-((3R)-3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid or a salt thereof;[11]3-((3S)-3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid or a salt thereof;[12]3-((3S)-3-((2-cyclohexylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid or a salt thereof;[13] a medicament comprising the compound of [1] or [2], or a saltthereof;[14] the medicament of [13], which is a retinol binding protein 4lowering drug;[15] the medicament of [13], which is a prophylactic or therapeuticagent for macular degeneration;[16] the compound of [1] or [2], or a salt thereof for use in theprophylaxis or treatment of macular degeneration and/or Stargardt'sdisease;[17] a method of lowering retinol binding protein 4 in a mammal,comprising administering an effective amount of the compound of [1] or[2], or a salt thereof to the mammal;[18] a method for the prophylaxis or treatment of macular degenerationand/or Stargardt's disease in a mammal, comprising administering aneffective amount of the compound of [1] or [2], or a salt thereof to themammal;[19] use of the compound of [1] or [2], or a salt thereof in producing aprophylactic or therapeutic agent for macular degeneration and/orStargardt's disease.

Effect of the Invention

According to the present invention, a prophylactic or therapeutic agentfor a disease or condition mediated by an increase in RBP4 or retinolsupplied by RBP4 such as age-related macular degeneration, Stargardt'sdisease and the like is provided.

DETAILED DESCRIPTION OF THE INVENTION

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, zo cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl. In the present specification, examplesof the “C₆₋₁₄ aryl group” include phenyl, 1-naphthyl, 2-naphthyl,1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl. In the presentspecification, examples of the “C₇₋₁₆ aralkyl-carbonyl group” includephenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following substituent group A.

[Substituent Group A]

(1) a halogen atom,(2) a nitro group,(3) a cyano group,(4) an oxo group,(5) a hydroxy group,(6) an optionally halogenated C₁₋₆ alkoxy group,(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),(14) a mono- or di-C_(L-6) alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated C₁₋₆ alkylthio group,(21) a 5- to 14-membered aromatic heterocyclic group,(22) a 3- to 14-membered non-aromatic heterocyclic group,(23) a formyl group,(24) a carboxy group,(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,(26) a C₆₋₁₄ aryl-carbonyl group,(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a C₁₋₆ alkoxy-carbonyl group,(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),(32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,(39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),(44) an amino group,(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),(49) a formylamino group,(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,N-acetyl-N-methylamino),(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),(57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group,(59) a C₂₋₆ alkynyl group,(60) a C₃₋₁₀ cycloalkyl group,(61) a C₃₋₁₀ cycloalkenyl group and(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom. Preferable examples of the “aromaticheterocyclic group” include 5- or 6-membered monocyclic aromaticheterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl,tetrazolyl, triazinyl and the like; and 8- to 14-membered fusedpolycyclic (preferably bi or tricyclic) aromatic heterocyclic groupssuch as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl,imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl,pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl,imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl,furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl,naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl,1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include the “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the aforementioned substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl)amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl)aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a(C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl)amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally zo substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆-14 aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”. Preferable examples of the optionally substituted hydroxygroup include a hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxygroup (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), aC₃₋₁₀ cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group(e.g., phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “hydrocarbon ring” includea C₆₋₁₄ aromatic hydrocarbon ring, C₃- to cycloalkane and C₃₋₁₀cycloalkene.

In the present specification, examples of the “C₆₋₁₄ aromatichydrocarbon ring” include benzene and naphthalene. In the presentspecification, examples of the “C₃₋₁₀ cycloalkane” include cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.

In the present specification, examples of the “C₃₋₁₀ cycloalkene”include cyclopropene, cyclobutene, cyclopentene, cyclohexene,cycloheptene and cyclooctene.

In the present specification, examples of the “heterocycle” include anaromatic heterocycle and a non-aromatic heterocycle, each containing, asa ring-constituting atom besides carbon atom, 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, examples of the “aromatic heterocycle”include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “aromatic heterocycle” include5- or 6-membered monocyclic aromatic heterocycles such as thiophene,furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole,isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole,tetrazole, triazine and the like; and 8- to 14-membered fused polycyclic(preferably bi or tricyclic) aromatic heterocycles such asbenzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole,benzothiazole, benzisothiazole, benzotriazole, imidazopyridine,thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine,oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine,thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine,oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine,pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole,isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole,β-carboline, phenanthridine, acridine, phenazine, phenothiazine,phenoxazine and the like.

In the present specification, examples of the “non-aromatic heterocycle”include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “non-aromatic heterocycle”include 3- to 8-membered monocyclic non-aromatic heterocycles such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,tetrahydropyridine, dihydropyridine, dihydrothiopyran,tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,azepanine, diazepane, azepine, azocane, diazocane, oxepane and the like;and 9- to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocycles such as dihydrobenzofuran,dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole,dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene,tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline,isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine,tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine,hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine,tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole,tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine,tetrahydrothioxanthene, octahydroisoquinoline and the like.

In the present specification, examples of the “nitrogen-containingheterocycle” include the “heterocycle” containing at least one nitrogenatom as a ring-constituting atom.

In the present specification, as the “ring” of the “optionallysubstituted ring”, the above-mentioned “hydrocarbon ring” and“heterocycle” can be mentioned and, as the substituent thereof, theabove-mentioned “substituent” can be mentioned.

Each symbol in the formula (I) is defined in detail below.

Ring A shows an optionally further substituted benzene ring.

The “benzene ring” of the “optionally further substituted benzene ring”for ring A is optionally further substituted at substitutableposition(s) by 1 to 4 (preferably 1 or 2) substituents other than R¹group and HOOC—CR²R³—CO-ring B—CH₂—O— group.

Examples of such “substituent” include halogen atom (e.g., fluorine,chlorine, bromine, iodine), optionally halogenated C₁₋₆ alkyl group(e.g., methyl, ethyl, isopropyl, trifluoromethyl), C₃₋₆ cycloalkyl group(e.g., cyclopropyl).

As ring A, a benzene ring not further substituted, that is, a benzenering not further substituted by a substituent other than a R¹ group andan HOOC—CR²R³—CO-ring B—CH₂—O— group is preferable. In the presentspecification, a benzene ring not further substituted (not furthersubstituted by a substituent other than a R¹ group and anHOOC—CR²R³—CO-ring B—CH₂—O— group) for ring A is sometimes to be simplyabbreviated as a “benzene ring”.

In another embodiment of the present invention, ring A is preferably abenzene ring optionally further substituted by a substituent selectedfrom a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and aC₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl).

R is a hydrogen atom or a C₁₋₆ alkyl group.

Examples of the “C₁₋₆ alkyl group” for R include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

R is preferably a hydrogen atom.

R¹ is a C₃₋₆ cycloalkyl group optionally substituted by substituent(s)selected from a fluorine atom and an optionally substituted alkyl group.

As R¹, a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl) optionally substituted an optionallysubstituted alkyl group (preferably, a C₁₋₆ alkyl group; e.g., methyl)is preferable, and a C₃₋₆ cycloalkyl group (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl) optionally substituted by an alkylgroup (preferably, C₁₋₆ alkyl group; e.g., methyl) optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine atom) is morepreferable.

In another embodiment of the present invention, R¹ is preferably a C₃₋₆cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl) optionally substituted by substituent(s) selected from aC₁₋₆ alkyl group (e.g., methyl) optionally substituted by a fluorineatom.

Ring B is an optionally further substituted pyrrolidine ring.

The “pyrrolidine ring” of the “optionally further substitutedpyrrolidine ring” for ring B is optionally further substituted atsubstitutable position(s) by 1 to 4 (preferably 1 or 2) substituentsother than R¹-ring A-O—CH₂— group and HOOC—CR²R³—CO— group.

Examples of the “substituent” include a halogen atom (e.g., fluorine),and an optionally halogenated C₁₋₆ alkyl group (e.g., methyl, ethyl,trifluoromethyl).

As ring B, pyrrolidine ring not further substituted, that is, apyrrolidine ring not substituted by a substituent other than R¹-ringA-O—CH₂— group and HOOC—CR²R³—CO— group is preferable. In the presentspecification, a pyrrolidine ring not further substituted (not furthersubstituted by a substituent other than R¹-ring A-O—CH₂— group andHOOC—CR²R³—CO— group) for ring B is sometimes to be simply abbreviatedas a “pyrrolidine ring”.

In another embodiment of the present invention, ring B is preferably apyrrolidine ring optionally further substituted by a substituentselected from a fluorine atom and a C₁₋₆ alkyl group (e.g., methyl,ethyl).

R² and R³ are each independently a hydrogen atom or a substituent, or R²and R³ are optionally joined to form an optionally substituted ring.

Examples of the “substituent” for R² or R³ include a halogen atom (e.g.,fluorine), and an optionally halogenated C₁₋₆ alkyl group (e.g., methyl,ethyl, propyl, trifluoromethyl).

Examples of the “ring” of the optionally substituted ring optionallyformed by R² and R³ in combination include a C₃₋₁₀ cycloalkane ring(e.g., cyclopropane ring, cyclobutane ring, cyclopentane ring,cyclohexane ring), a 3- to 8-membered monocyclic non-aromaticheterocycle (e.g., oxetane ring, tetrahydrofuran ring, tetrahydropyranring), and examples of the “substituent” thereof include a halogen atom(e.g., fluorine), and an optionally halogenated C₁₋₆ alkyl group (e.g.,methyl, ethyl, trifluoromethyl).

As R² and R³, a hydrogen atom is preferable for each.

In another embodiment of the present invention, R² and R³ are preferablyeach independently a hydrogen atom, a halogen atom (e.g., fluorine), ora C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl), or R² and R³ areoptionally joined to form a C₃₋₄ cycloalkane ring (e.g., cyclopropanering, cyclobutane ring).

Preferable examples of compound (I) include the following compounds.

[Compound I-1]

Compound (I) wherein

ring A is a benzene ring optionally further substituted by a substituentselected from a halogen atom (e.g., fluorine, chlorine, bromine, iodine)and a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl);

R is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl, ethyl);

R¹ is a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl) optionally substituted by substituent(s)selected from a C₁₋₆ alkyl group (e.g., methyl) optionally substitutedby a fluorine atom;

ring B is a pyrrolidine ring optionally further substituted by asubstituent selected from a fluorine atom and a C₁₋₆ alkyl group (e.g.,methyl, ethyl); and

R² and R³ are each independently a hydrogen atom, a halogen atom (e.g.,fluorine), or a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl), or R²and R³ are optionally joined to form a C₃₋₄ cycloalkane ring (e.g.,cyclopropane ring, cyclobutane ring).

[Compound I-2]

Compound (I) wherein

ring A is a benzene ring;

R is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl, ethyl);

R¹ is a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl) optionally substituted an optionallysubstituted Ca-6 alkyl group (e.g., methyl);

ring B is a pyrrolidine ring; and

R² and R³ are both hydrogen atoms.

[Compound I-3]

Compound (I) wherein

ring A is a benzene ring;

R is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl, ethyl);

R¹ is a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl) optionally substituted by a C₁₋₆ alkyl group(e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine atom);

ring B is a pyrrolidine ring;

R² and R³ are both hydrogen atoms.

Specific examples of Compound (I) include compounds of Examples 1 to 34,more preferably the compounds of Examples 1 to 7, particularlypreferably the compounds of Examples 2, 4, 5, 6 and 7.

When compound (I) is a salt, examples thereof include metal salts,ammonium salts, salts with organic bases, salts with inorganic acids,salts with organic acids, salts with basic or acidic amino acids. Aspreferable examples of the metal salt, alkali metal salts such as sodiumsalt, potassium salt and the like; alkaline earth metal salts such ascalcium salt, magnesium salt, barium salt and the like; aluminum saltcan be mentioned. As preferable examples of the salts with organicbases, salts with trimethylamine, triethylamine, pyridine, picoline,2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,cyclohexylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine and thelike can be mentioned. As preferable examples of the salts withinorganic acids, salts with hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid and the like can be mentioned. Aspreferable examples of the salts with organic acids, salts with formicacid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid,oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like can be mentioned. As preferableexamples of the salts with basic amino acids, salts with arginine,lysine, ornithine and the like can be mentioned. As preferable examplesof the salts with acidic amino acids, salts with aspartic acid, glutamicacid and the like can be mentioned.

Of these, pharmaceutically acceptable salts are preferable. For example,when a compound has an acidic functional group therein, inorganic saltssuch as alkali metal salts (e.g., sodium salt, potassium salt and thelike), alkaline earth metal salts (e.g., calcium salt, magnesium salt,and the like) and the like, ammonium salt and the like can be mentioned.When a compound has a basic functional group therein, salts withinorganic acids such as hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid and the like, and salts withorganic acids such as acetic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like can be mentioned.

In the present specification, compound (I), crystal of compound (I),prodrug of compound (I) and the like are sometimes collectivelyabbreviated as “the compound of the present invention”.

[Production Method]

The production method of the compound of the present invention isexplained in the following.

The starting materials and reagents used in each step in the followingproduction method, and the obtained compounds each may form a salt.Examples of the salt include those similar to the aforementioned saltsof the compound of the present invention and the like.

When the compound obtained in each step is a free compound, it can beconverted to a desired salt by a method known per se. Conversely, whenthe compound obtained in each step is a salt, it can be converted to afree form or a desired other kind of salt by a method known per se.

The compound obtained in each step can also be used for the nextreaction as a reaction mixture thereof or after obtaining a crudeproduct thereof. Alternatively, the compound obtained in each step canbe isolated and/or purified from the reaction mixture by a separationmeans such as concentration, crystallization, recrystallization,distillation, solvent extraction, fractionation, chromatography and thelike according to a conventional method.

When the starting materials and reagent compounds of each step arecommercially available, the commercially available products can be usedas they are.

In the reaction of each step, while the reaction time varies dependingon the reagents and solvents to be used, unless otherwise specified, itis generally 1 min to 48 hr, preferably 10 min to 8 hr.

In the reaction of each step, while the reaction temperature variesdepending on the reagents and solvents to be used, unless otherwisespecified, it is generally −78° C. to 300° C., preferably −78° C. to150° C.

In the reaction of each step, while the pressure varies depending on thereagents and solvents to be used, unless otherwise specified, it isgenerally 1 atm to 20 atm, preferably 1 atm to 3 atm.

In the reaction of each step, for example, microwave synthesizers suchas Initiator manufactured by Biotage and the like are sometimes used.While the reaction temperature varies depending on the reagents andsolvents to be used, unless otherwise specified, it is generally roomtemperature to 300° C., preferably 50° C. to 250° C. While the reactiontime varies depending on the reagents and solvents to be used, unlessotherwise specified, it is generally 1 min to 48 hr, preferably 1 min to8 hr.

In the reaction of each step, unless otherwise specified, a reagent isused in 0.5 equivalent to 20 equivalents, preferably 0.8 equivalent to 5equivalents, relative to the substrate. When a reagent is used as acatalyst, the reagent is used in 0.001 equivalent to 1 equivalent,preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate.When the reagent is also a reaction solvent, the reagent is used in asolvent amount.

In the reaction of each step, unless otherwise specified, it isperformed without solvent or by dissolving or suspending in a suitablesolvent. Specific examples of the solvent include those described inExamples and the following.

alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol andthe like;ethers: diethyl ether, diphenyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like;aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;saturated hydrocarbons: cyclohexane, hexane and the like; amides:N,N-dimethylformamide, N-methylpyrrolidone and the like;halogenated hydrocarbons: dichloromethane, carbon tetrachloride and thelike;nitriles: acetonitrile and the like;sulfoxides: dimethyl sulfoxide and the like;aromatic organic bases: pyridine and the like;acid anhydrides: acetic anhydride and the like;organic acids: formic acid, acetic acid, trifluoroacetic acid and thelike;inorganic acids: hydrochloric acid, sulfuric acid and the like; esters:ethyl acetate and the like;ketones: acetone, methyl ethyl ketone and the like; and water. Two ormore kinds of the above-mentioned solvents may be used by mixing at anappropriate ratio.

When a base is used in the reaction of each step, for example, basesshown below or those described in Examples are used.

inorganic bases: sodium hydroxide, magnesium hydroxide and the like;basic salts: sodium carbonate, calcium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium phosphate, cesium carbonateand the like;organic bases: triethylamine, diethylamine, pyridine,4-dimethylaminopyridine, N,N-dimethylaniline,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole, piperidine and the like;metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;alkali metal hydrides: sodium hydride and the like;metal amides: sodium amide, lithium diisopropyl amide, lithiumhexamethyl disilazide and the like; andorganic lithiums: n-butyllithium and the like.

When an acid or acidic catalyst is used in the reaction of each step,for example, acids and acidic catalysts shown below or those describedin Examples are used.

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid and the like;organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; andLewis acids: boron trifluoride diethyl ether complex, zinc iodide,anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ironchloride and the like.

Unless otherwise specified, the reaction of each step is performedaccording to a method known per se, for example, the methods describedin Jikken Kagaku Kouza 5th edition, vol. 13-vol. 19 (The ChemicalSociety of Japan ed.); Shinjikken Kagaku Kouza (Courses in ExperimentalChemistry), vol. 14-vol. 15 (The Chemical Society of Japan ed.); FineOrganic Chemistry rev. 2nd edition (L. F. Tietze, Th. Eicher, NANKODO);rev. Organic Name Reactions, Their Mechanism and Essence (Hideo Togo,Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & SonsInc); Modern Organic Synthesis in the Laboratory, A Collection ofStandard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY);Comprehensive Heterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier JapanKK); Strategic Applications of Named Reactions in Organic Synthesis(translation supervisor Kiyoshi Tomioka, KAGAKUDOJIN); ComprehensiveOrganic Transformations (VCH Publishers Inc.), 1989 and the like, or themethods described in the Examples.

In each step, protection or deprotection of a functional group isperformed by the method known per se, for example, the methods describedin “Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W.Greene, Peter G. M. Wuts) Wiley-Interscience, 2007; “Protecting Groups3rd Ed.” (P. J. Kocienski) Thieme, 2004 and the like, or the methodsdescribed in the Examples.

Examples of the protecting group of the hydroxyl group of alcohol andthe like and a phenolic hydroxyl group include ether protecting groupssuch as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether,tetrahydropyranyl ether and the like; carboxylate protecting groups suchas acetate and the like; sulfonate ester protecting groups such asmethanesulfonate ester and the like; carbonate ester protecting groupssuch as t-butylcarbonate and the like, and the like.

Examples of the protecting group of the carbonyl group of aldehydeinclude acetal protecting groups such as dimethyl acetal and the like;cyclic acetal protecting groups such as cyclic 1,3-dioxane and the like,and the like.

Examples of the protecting group of the carbonyl group of ketone includeketal protecting groups such as dimethyl ketal and the like; cyclicketal protecting groups such as cyclic 1,3-dioxane and the like; oximeprotecting groups such as O-methyloxime and the like; hydrazoneprotecting groups such as N,N-dimethylhydrazone and the like, and thelike.

Examples of the carboxyl protecting group include ester protectinggroups such as methyl ester and the like; amide protecting groups suchas N,N-dimethylamide and the like, and the like.

Examples of the thiol protecting group include ether protecting groupssuch as benzyl thioether and the like; ester protecting groups such asthioacetate ester, thiocarbonate, thiocarbamate and the like, and thelike.

Examples of the protecting group of an amino group and an aromatichetero ring such as imidazole, pyrrole, indole and the like includecarbamate protecting groups such as benzyl carbamate and the like; amideprotecting groups such as acetamide and the like; alkylamine protectinggroups such as N-triphenylmethylamine and the like, sulfonamideprotecting groups such as methanesulfonamide and the like, and the like.

The protecting group can be removed by a method known per se, forexample, a method using acid, base, ultraviolet light, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyliodide, trimethylsilyl bromide), a reduction method and the like.

When a reduction reaction is performed in each step, examples of thereducing agent to be used include metal hydrides such as lithiumaluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutylaluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asborane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt;hydrogen; formic acid; triethylsilane and the like. When a carbon-carbondouble bond or triple bond is reduced, a method using a catalyst such aspalladium-carbon, Lindlar catalyst and the like.

When an oxidation reaction is performed in each step, examples of anoxidant to be used include peracids such as m-chloroperbenzoic acid(mCPBA), hydrogen peroxide, t-butyl hydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodic acids such as sodium periodate and thelike; high valent iodine reagents such as iodosylbenzene and the like;reagents containing manganese such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;reagents containing chrome such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagent and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;sulfur trioxide pyridine complex; osmium tetraoxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When a radical cyclization reaction is performed in each step, examplesof the radical initiator to be used include azo compounds such asazobisisobutyronitrile (AIBN) and the like; water-soluble radicalinitiators such as 4,4′-azobis-4-cyanopentanoic acid (ACPA) and thelike; triethylboron in the presence of air or oxygen; benzoyl peroxideand the like. In addition, examples of the radical reaction agent to beused include tributylstannane, tristrimethylsilylsilane,1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and thelike.

When the Wittig reaction is performed in each step, examples of theWittig reagent to be used include alkylidenephosphoranes and the like.Alkylidenephosphoranes can be prepared by a method known per se, forexample, by reacting a phosphonium salt with a strong base.

When the Horner-Emmons reaction is performed in each step, examples ofthe reagent to be used include phosphonoacetic acid esters such asmethyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and thelike; and bases such as alkali metal hydrides, organic lithiums and thelike.

When the Friedel-Crafts reaction is performed in each step, examples ofthe reagent to be used include a combination of Lewis acid and acidchloride or a combination of Lewis acid and alkylating agents (e.g.,alkyl halides, alcohol, olefins and the like). Alternatively, an organicacid and an inorganic acid can also be used instead of the Lewis acid,and acid anhydride such as acetic anhydride and the like can also beused instead of acid chloride.

When an aromatic nucleophilic substitution reaction is performed in eachstep, a nucleophilic agent (e.g., amines, imidazole and the like) and abase (e.g., basic salts, organic bases and the like) are used as thereagent.

When a nucleophilic addition reaction with carbanion; a nucleophilic1,4-addition reaction with carbanion (Michael addition reaction) or anucleophilic substitution reaction with carbanion is performed in eachstep, examples of the base to be used for developing carbanion includeorganic lithiums, metal alkoxides, inorganic bases, organic bases andthe like.

When the Grignard reaction is performed in each step, examples of theGrignard reagent include aryl magnesium halides such as phenyl magnesiumbromide and the like; and alkyl magnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared bya method known per se, for example, by reacting alkyl halide or arylhalide with metal magnesium in ether or tetrahydrofuran as a solvent.

When the Knoevenagel condensation reaction is performed in each step, anactive methylene compound held between two electron-withdrawing groups(e.g., malonic acid, diethyl malonate, malononitrile and the like) and abase (e.g., organic bases, metal alkoxides, inorganic bases) are used asthe reagents.

When the Vilsmeier-Haack reaction is performed in each step, phosphorylchloride and an amide derivative (e.g., N,N-dimethylformamide and thelike) are used as the reagents.

When an azidation reaction of alcohols, alkylhalides or sulfonate estersis performed in each step, examples of the azidation agent to be usedinclude diphenylphosphoryl azide (DPPA), trimethylsilylazide, sodiumazide and the like. For example, when alcohols are azidated, a methodusing diphenylphosphoryl azide and 1,8-diazabicyclo[5,4,0]undec-7-ene(DBU), a method using trimethylsilylazide and the Lewis acid and thelike can be employed.

When a reductive amination reaction is performed in each step, examplesof the reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, hydrogen, formic acid and the like. When thesubstrate is an amine compound, examples of the carbonyl compound to beused besides para-formaldehyde include aldehydes such as acetaldehydeand the like, ketones such as cyclohexanone and the like. When thesubstrate is a carbonyl compound, examples of the amines to be usedinclude ammonia, primary amines such as methylamine and the like;secondary amines such as dimethylamine and the like, and the like.

When the Mitsunobu reaction is performed in each step, azodicarboxylateesters (e.g., diethyl azodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD) and the like) and triphenylphosphine are used asthe reagents.

When an esterification reaction, amidation reaction or ureation reactionis performed in each step, examples of the reagent to be used includehalogenated acyl forms such as acid chloride, acid bromide and the like;and activated carboxylic acids such as acid anhydride, active esterform, sulfuric acid ester form and the like. Examples of the carboxylicacid activator include carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM) and the like; carbonate ester condensingagents such as 1,1-carbonyldiimidazole (CDI) and the like;diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent);2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionylchloride; lower alkyl haloformates such as ethyl chloroformate and thelike; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; a combination thereof and thelike. When a carbodiimide condensing agent is used, additives such as1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP) and the like can be further added to thereaction.

When a coupling reaction is performed in each step, examples of themetal catalyst to be used include palladium compounds such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,palladium(II) acetate and the like; nickel compounds such astetrakis(triphenylphosphine)nickel(0) and the like; rhodium compoundssuch as tris(triphenylphosphine)rhodium(III) chloride and the like; acobalt compound; copper compounds such as copper oxide, copper(I) iodideand the like; a platinum compound and the like. A base may be furtheradded to the reaction and examples of such base include inorganic bases,basic salts and the like.

When a thiocarbonylation reaction is performed in each step,diphosphorus pentasulfide is representatively used as athiocarbonylating agent. Besides diphosphorus pentasulfide, a reagenthaving a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson reagent) and the like may also be used.

When the Wohl-Ziegler reaction is performed in each step, examples ofthe halogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. Furthermore, the reaction can be accelerated byadding heat, light, radical initiators such as benzoyl peroxide,azobisisobutyronitrile and the like to the reaction.

When a halogenating reaction of a hydroxy group is performed in eachstep, examples of the halogenating agent to be used include acid halideof hydrohalic acid and inorganic acid; specifically, hydrochloric acid,thionyl chloride, phosphorus oxychloride and the like for chlorination,and 48% hydrobromic acid and the like for bromination. In addition, amethod of obtaining a halogenated alkyl form from alcohol by reactingwith triphenylphosphine and carbon tetrachloride or carbon tetrabromide,and the like may be used. Alternatively, a method of synthesizing ahalogenated alkyl form via a two-step reaction including conversion ofalcohol to sulfonic acid ester, and reacting same with lithium bromide,lithium chloride or sodium iodide may also be used.

When the Arbuzov reaction is performed in each step, examples of thereagent to be used include alkyl halides such as ethyl bromoacetate andthe like; and phosphites such as triethyl phosphite,tri(isopropyl)phosphite and the like.

When a sulfonation reaction is performed in each step, examples of thesulfonylating agent to be used include methanesulfonyl chloride,p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonicanhydride and the like.

When hydrolysis is performed in each step, an acid or a base is used asthe reagent. In addition, when acid hydrolysis of t-butyl ester isperformed, formic acid, triethylsilane and the like are sometimes addedto reductively trap the by-produced t-butyl cation.

When a dehydrating reaction is performed in each step, examples of thedehydrating agent to be used include sulfuric acid, phosphoruspentaoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina, polyphosphoric acid and the like.

When nitration reaction is performed in each step, examples of thenitrating agent to be used include nitric acid, fuming nitric acid, andcopper nitrate. The reaction is activated by concentrated sulfuric acid,acetic anhydride and the like.

When halogenation reaction is performed in each step, examples of thehalogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), iodinemonochloride, iodine, bromine, sulfuryl chloride and the like can bementioned. In this reaction, an additive such as trifluoroacetic acidand the like may be used for the activation of a halogenating agent.

When acylation reaction is performed in each step, amidation reaction,ureation reaction, carbamation reaction, thiocarbamation reaction andthe like are performed. When carbamation reaction or thiocarbamationreaction is performed, examples of the reagent to be used includetriphosgene, carbonate condensing agents such as 1,1-carbonyldiimidazole(CDI) and the like, chlorocarbonates, chlorocarbonic acid thio esters,isothiocyanates and the like

When cyclization reaction is performed in each step, it is performed bythe Mitsunobu reaction or an alkylation reaction. When an alkylationreaction is performed, a base is used as the reagent.

Compound (14) can be produced from compound (1) by the method shown inscheme 1 or a method analogous thereto or the method described in theExamples. In the formula, R⁴ shows an optionally substituted hydrocarbongroup.

Compound (2) can be produced by a trifluoromethylation reaction ofcompound (1) and trimethyl(trifluoromethyl)silane. As the solvent to beused, N,N-dimethylformamide and the like can be mentioned.

As Compound (1), a commercially available product is directly used, orcan be produced according to a method known per se, or a methodanalogous thereto.

Compound (3) can be produced by deprotection of compound (2) andtetrabutylammonium fluoride. As the solvent to be used, tetrahydrofuranand the like can be mentioned.

Compound (4) can be produced by an oxidation reaction of compound (3)and a Dess-Martin reagent. As the solvent to be used, dimethylsulfoxide,dichloromethane and the like can be mentioned.

Compound (5) can be produced by a methylenation reaction of compound(4), methyltriphenylphosphonium bromide and a base. As the solvent to beused, tetrahydrofuran and the like can be mentioned.

Compound (6) can be produced by a ring formation reaction ofdiazomethane prepared by compound (5), 1-methyl-1-nitrosourea and abase. Examples of the base to be used include potassium hydroxide, andexamples of the solvent include water, diethyl ether and the like.

Compound (7) can be produced by a cyclopropane ring formation reactionby heating compound (6). As the solvent to be used, xylene and the likecan be mentioned.

Compound (8) can be produced by a demethylation reaction of compound (7)and boron tribromide. As the solvent to be used, dichloromethane and thelike can be mentioned.

Compound (10) can be produced by a tosylation reaction of compound (9)and 4-methylbenzene-1-sulfonyl chloride. As the solvent to be used,pyridine and the like can be mentioned.

Compound (11) can be produced by an alkylation reaction with phenol ofcompound (10), compound (8) and a base. Examples of the base to be usedinclude potassium phosphate and the like, and examples of the solventinclude N,N-dimethylformamide and the like.

Compound (12) can be produced by a deprotection of compound (11) and anacid. Examples of the acid to be used include hydrochloric acid and thelike, and examples of the solvent include 1,4-dioxane and the like.

Compound (13) can be produced by a condensation reaction of compound(12), 3-ethoxy-3-oxopropanoic acid, HATU and a base. Examples of thebase to be used include N,N-diisopropylethylamine and the like, andexamples of the solvent include N,N-dimethylformamide and the like.

Compound (14) can be produced by hydrolysis reaction of compound (13)and a base. Examples of the base to be used include lithium hydroxideand the like, and examples of the solvent include water, ethanol and thelike.

Compound (21) can be produced from compound (15) by the method shown inscheme 2 or a method analogous thereto or the method described in theExamples. In the formula, R⁴ shows an optionally substituted hydrocarbongroup.

Compound (16) can be produced by an alkylation reaction of compound(15), 3-bromo-2-methylpropene and a base. Examples of the base to beused include potassium carbonate and the like, and examples of thesolvent include acetone and the like.

As compound (15), a commercially available product is directly used, orcan be produced according to a method known per se, or a methodanalogous thereto.

Compound (17) can be produced by a cyclopropane ring formation reactionof compound (16), tert-butyllithium andN,N,N′,N′-tetramethylethylenediamine. As the solvent to be used, diethylether and the like can be mentioned.

Compound (18) can be produced by an alkylation reaction of compound(17), compound (10) and a base. Examples of the base to be used includepotassium phosphate and the like, and examples of the solvent includeN,N-dimethylformamide and the like.

Compound (19) can be produced by deprotection of compound (18) and anacid. Examples of the acid to be used include hydrochloric acid and thelike, and examples of the solvent include 1,4-dioxane and the like.

Compound (20) can be produced by a condensation reaction of compound(19), 3-ethoxy-3-oxopropanoic acid, HATU and a base. Examples of thebase to be used include N,N-diisopropylethylamine and the like, andexamples of the solvent include N,N-dimethylformamide and the like.

Compound (21) can be produced by hydrolysis reaction of compound (20)and a base. Examples of the base to be used include lithium hydroxideand the like, and examples of the solvent include water, ethanol and thelike.

Compound (27) can be produced from compound (15) by the method shown inscheme 3 or a method analogous thereto or the method described in theExamples. In the formula, R⁴ is an is optionally substituted hydrocarbongroup.

Compound (22) can be produced by an alkylation reaction of compound(15), n-butyllithium and cyclobutanone. As the solvent to be used,diethyl ether and the like can be mentioned.

Compound (23) can be produced by a reduction reaction of compound (22),triethylsilane and trifluoroacetic acid. As the solvent to be used,dichloromethane and the like can be mentioned.

Compound (24) can be produced by an alkylation reaction of compound(23), compound (10) and a base. Examples of the base to be used includepotassium phosphate and the like, and examples of the solvent includeN,N-dimethylformamide and the like.

Compound (25) can be produced by a deprotection of compound (24) and anacid. Examples of the acid to be used include hydrochloric acid and thelike, and examples of the solvent include 1,4-dioxane and the like.

Compound (26) can be produced by a condensation reaction of compound(25), 3-ethoxy-3-oxopropanoic acid, HATU and a base. Examples of thebase to be used include N,N-diisopropylethylamine and the like, andexamples of the solvent include N,N-dimethylformamide and the like.

Compound (27) can be produced by hydrolysis reaction of compound (26)and a base. Examples of the base to be used include lithium hydroxideand the like, and examples of the solvent include water, ethanol and thelike.

Compound (32) can be produced from compound (28) by the method shown inscheme 4 or a method analogous thereto or the method described in theExamples. In the formula, R⁴ shows an optionally substituted hydrocarbongroup.

Compound (29) can be produced by an alkylation reaction of compound(28), compound (10) and a base. Examples of the base to be used includepotassium-phosphate and the like, and examples of the solvent includeN,N-dimethylformamide and the like.

As compound (28), a commercially available product is directly used, orcan be produced according to a method known per se, or a methodanalogous thereto.

Compound (30) can be produced by deprotection of compound (29) and anacid. Examples of the acid to be used include hydrochloric acid and thelike, and examples of the solvent include ethyl acetate and the like.

Compound (31) can be produced by a condensation reaction of compound(30), 3-ethoxy-3-oxopropanoic acid,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBtmonohydrate and a base. Examples of the base to be used includetriethylamine and the like, and examples of the solvent includeN,N-dimethylformamide and the like.

Compound (32) can be produced by hydrolysis reaction of compound (31)and a base. Examples of the base to be used include lithium hydroxideand the like, and examples of the solvent include water, ethanol,tetrahydrofuran and the like.

Compound (37) can be produced from compound (33) by the method shown inscheme 5 or a method analogous thereto or the method described in theExamples. In the formula, R⁴ shows an optionally substituted hydrocarbongroup.

Compound (34) can be produced by an alkylation reaction of compound(33), compound (10) and a base. Examples of the base to be used includepotassium phosphate and the like, and examples of the solvent includeN,N-dimethylformamide and the like.

As compound (33), a commercially available product is directly used, orcan be produced according to a method known per se, or a methodanalogous thereto.

Compound (35) can be produced by deprotection of compound (34) and anacid. Examples of the acid to be used include hydrochloric acid and thelike, and examples of the solvent include ethyl acetate and the like.

Compound (36) can be produced by a condensation reaction of compound(35), 3-ethoxy-3-oxopropanoic acid,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBtmonohydrate and a base. Examples of the base to be used includetriethylamine and the like, and examples of the solvent includeN,N-dimethylformamide and the like.

Compound (37) can be produced by hydrolysis reaction of compound (36)and a base. Examples of the base to be used include lithium hydroxideand the like, and examples of the solvent include water, ethanol,tetrahydrofuran and the like.

Compound (44) can be produced from compound (38) by a method shown inscheme 6 or a method analogous thereto or the method described in theExamples. In the formula, R⁴ is an optionally substituted hydrocarbongroup.

Compound (39) can be produced by a tosylation reaction of compound (38)and 4-methylbenzene-1-sulfonyl chloride. As the solvent to be used,pyridine and the like can be mentioned.

As compound (38), a commercially available product is directly used, orcan be produced according to a method known per se, or a methodanalogous thereto.

Compound (41) can be produced by an alkylation reaction of compound(40), compound (39) and a base. Examples of the base to be used includepotassium phosphate and the like, and examples of the solvent includeN,N-dimethylformamide and the like.

As compound (40), a commercially available product is directly used, orcan be produced according to a method known per se, or a methodanalogous thereto.

Compound (42) can be produced by deprotection of compound (41) and anacid. Examples of the acid to be used include hydrochloric acid and thelike, and examples of the solvent include ethyl acetate and the like.

Compound (43) can be produced by a condensation reaction of compound(42), 3-ethoxy-3-oxopropanoic acid,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBtmonohydrate and a base. Examples of the base to be used includetriethylamine and the like, and examples of the solvent includeN,N-dimethylformamide and the like.

Compound (44) can be produced by hydrolysis reaction of compound (43)and a base. Examples of the base to be used include lithium hydroxideand the like, and examples of the solvent include water, ethanol and thelike.

Compound (51) can be produced from compound (45) by a method shown inscheme 7 or a method analogous thereto or the method described in theExamples. In the formula, R⁴ is an optionally substituted hydrocarbongroup.

Compound (46) can be produced by a tosylation reaction of compound (45)and 4-methylbenzene-1-sulfonyl chloride. As the solvent to be used,pyridine and the like can be mentioned.

As compound (45), a commercially available product is directly used, orcan be produced according to a method known per se, or a methodanalogous thereto.

Compound (48) can be produced by an alkylation reaction of compound(47), compound (46) and a base. Examples of the base to be used includepotassium phosphate and the like, and examples of the solvent includeN,N-dimethylformamide and the like.

As compound (47), a commercially available product is directly used, orcan be produced according to a method known per se, or a methodanalogous thereto.

Compound (49) can be produced by deprotection of compound (48) and anacid. Examples of the acid to be used include zo hydrochloric acid andthe like, and examples of the solvent include ethyl acetate and thelike.

Compound (50) can be produced by a condensation reaction of compound(49), 3-ethoxy-3-oxopropanoic acid,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBtmonohydrate and a base. Examples of the base to be used includetriethylamine and the like, and examples of the solvent includeN,N-dimethylformamide and the like.

Compound (51) can be produced by hydrolysis reaction of compound (50)and a base. Examples of the base to be used include lithium hydroxideand the like, and examples of the solvent include water, ethanol and thelike.

When compound (I) contains optical isomer, stereoisomer, positionalisomer, or rotamer, these are also encompassed in compound (I), and canbe obtained as a single product by synthesis methods and separationmethods (e.g., concentration, solvent extraction, column chromatography,recrystallization etc.) known per se. For example, when compound (I)contains an optical isomer, an optical isomer resolved from the compoundis also encompassed in compound (I).

An optical isomer can be produced by a method known per se. To bespecific, an optical isomer is obtained using an optically activesynthetic intermediate, or by optical resolution of a racemate of thefinal product by a conventional method.

The method of optical resolution may be a method known per se, such as afractional recrystallization method, a chiral column method, adiastereomer method etc.

Compound (I) may be a crystal.

The crystal of compound (I) can be produced by crystallization ofcompound (I) by applying a crystallization method known per se.

Examples of the crystallization method include a method ofcrystallization from a solution, a method of crystallization from vapor,and a method of crystallization from a molten form.

As the analysis method of the obtained crystal, a crystal analysismethod by powder X-ray diffraction is general. Furthermore, as a methodof determining the crystal orientation, a mechanical method, an opticalmethod and the like can also be mentioned.

The crystal of compound (I) obtained by the above-mentioned productionmethod has high purity, high quality, and low hygroscopicity, is notdenatured even after preservation under general conditions for a longterm, and is extremely superior in stability. It is also superior inbiological properties (e.g., pharmacokinetics (absorption, distribution,metabolism, excretion), efficacy expression), and thus is extremelyuseful as a medicament.

A prodrug of compound (I) means a compound which is converted to thecompound (I) with a reaction due to an enzyme, an gastric acid, etc.under the physiological condition in the living body, that is, acompound which is converted to the compound (I) with oxidation,reduction, hydrolysis, etc. according to an enzyme; a compound which isconverted to the compound (I) by hydrolysis etc. due to gastric acid,etc. A prodrug for compound (I may be a compound obtained by subjectingan amino group in compound (I) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to an acylation, alkylation, phosphorylation orboration [e.g., a compound obtained by subjecting an hydroxy group incompound (I) to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.]; a compound obtained bysubjecting a carboxyl group in compound (I) to an esterification oramidation [e.g., a compound obtained by subjecting a carboxyl group incompound (I) to an ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification andmethylamidation, etc.] and the like. Any of these compounds can beproduced from compound (I) by a method known per se.

A prodrug for compound (I) may also be one which is converted tocompound (I) under physiological conditions, such as those described in“Development of Pharmaceutical Product”, Vol. 7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990)

Compound (I) may be any of a hydrate, a non-hydrate, a solvate and anon-solvate.

Compound (I) also encompasses a compound labeled with an isotope (e.g.,³H, ¹⁴C, ³⁵S, ¹²⁵I etc.) and the like.

Compound (I) also encompasses a deuterium conversion form wherein 1H isconverted to ²H(D).

Compound (I) also encompasses a tautomer.

Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystalsalt. Here, the cocrystal or cocrystal salt means a crystallinesubstance consisting of two or more particular substances which aresolids at room temperature, each having different physical properties(e.g., structure, melting point, heat of melting, hygroscopicity,solubility, stability etc.). The cocrystal and cocrystal salt can beproduced by cocrystallization method known per se.

Compound (I) may also be used as a PET tracer.

The compound of the present invention has a superior retinol bindingprotein 4-lowering action. The compound of the present invention alsohas a superior retinol binding protein 4 binding inhibitory action(retinol binding protein 4-TTR (transthyretin) binding inhibitoryaction).

Therefore, the compound of the present invention is useful as a safemedicament based on these actions. For example, the medicament of thepresent invention containing the compound of the present invention canbe used as a prophylactic or therapeutic agent for retinol bindingprotein 4 associated diseases in mammals (e.g., mouse, rat, hamster,rabbit, cat, dog, bovine, sheep, monkey, human etc.).

When used in the present specification, treatment also includessuppression of the progression of a disease or condition.

Specifically, the compound of the present invention can be usedprophylactic or therapeutic agent for a disease or condition mediated byan increase in RBP4 or retinol supplied by RBP4, for example, maculardegeneration (e.g., dry (atrophic or non-vascular) age-related maculardegeneration, exudative (wet or neovascular) age-related maculardegeneration), geographic atrophy and/or denaturation of photoreceptor,macular dystrophy and retinal dystrophy, retinopathy (e.g., diabeticretinopathy, retinopathy of prematurity), retinitis pigmentosa, retinalvein occlusion, retinal artery obstruction, glaucoma, or Stargardt'sdisease (Stargardt disease).

The compound of the present invention can also be used as an agent forthe prophylaxis or treatment of obesity, hyperlipidemia (e.g.,hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia,hypo HDL-cholesterolemia, postprandial hyperlipidemia), hypertension,cardiac failure, diabetic complications [e.g., neuropathy, nephropathy,retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy,osteopenia, hyperosmolar diabetic coma, infections (e.g., respiratoryinfection, urinary tract infection, gastrointestinal infection, dermalsoft tissue infections, inferior limb infection), diabetic gangrene,xerostomia, hypacusis, cerebrovascular disorder, peripheral bloodcirculation disorder], metabolic syndrome, sarcopenia and the like.

The compound of the present invention can also be used as an agent forthe prophylaxis or treatment of, for example, osteoporosis, cachexia(e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia,hemopathic cachexia, endocrinopathic cachexia, infectious cachexia orcachexia induced by acquired immunodeficiency syndrome), fatty liver,polycystic ovary syndrome, renal disease (e.g., diabetic nephropathy,glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensivenephrosclerosis, end-stage renal disorder), muscular dystrophy,myocardial infarction, angina pectoris, cerebrovascular disorder (e.g.,cerebral infarction, cerebral apoplexy), Alzheimer's disease,Parkinson's disease, anxiety, dementia, insulin resistance syndrome,syndrome X, hyperinsulinemia, perception disorder in hyperinsulinemia,tumor (e.g., leukemia, breast-cancer, prostate cancer, skin cancer),irritable bowel syndrome, acute or chronic diarrhea, inflammatorydisease (e.g., chronic rheumatoid arthritis, spondylitis deformans,osteoarthritis, lumbago, gout, postoperative or post-traumaticinflammation, swelling, neuralgia, pharyngolaryngitis, bladderinflammation, hepatitis (including nonalcoholic steatohepatitis),pneumonia, pancreatitis, enteritis, inflammatory bowel disease(including inflammatory colitis), ulcerative colitis, gastric mucosainjury (including gastric mucosa injury caused by aspirin)), smallintestinal mucosa injury, malabsorption, testis dysfunction, visceralobesity syndrome, and sarcopenia.

The compound of the present invention can also be used as an agent forlowering the level of serum retinol, serum RBP (retinol binding protein)and/or serum TTR (transthyretin) and can also be used as, for example, aprophylactic or therapeutic agent for hyperretinolemia (excess serumretinol level).

The compound of the present invention can also be used for the secondaryprevention or prevention of the progression of the above-mentionedvarious diseases (e.g., cardiovascular events such as myocardialinfarction and the like).

The compound of the present invention can be directly used as themedicament of the present invention, or as a pharmaceutical compositionformed by mixing with a pharmacologically acceptable carrier by a meansknown per se, which is generally used for a production method of apharmaceutical preparation.

The medicament of the present invention can be safely administeredorally or parenterally to mammals (e.g., human, monkey, bovine, horse,swine, mouse, rat, hamster, rabbit, cat, dog, sheep, goat etc.).

As a medicament containing the compound of the present invention, thecompound of the present invention can be used alone or as apharmaceutical composition mixed with pharmacologically acceptablecarriers, according to a method known per se as a production method of apharmaceutical preparation (e.g., methods described in the JapanesePharmacopeia, etc.). A medicament containing the compound of the presentinvention can be safely administered in the form of, for example, tablet(including sugar-coated tablet, film-coated tablet, sublingual tablet,orally disintegrating tablet, buccal tablet and the like), pill, powder,granule, capsule (including soft capsule, microcapsule), troche, syrup,liquid, emulsion, suspension, release control preparation (e.g.,immediate-release preparation, sustained-release preparation,sustained-release microcapsule), aerosol, film (e.g., orallydisintegrating film, oral mucosa-adhesive film), injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection), drip infusion, transdermal absorption typepreparation, cream, ointment, lotion, adhesive preparation, suppository(e.g., rectal suppository, vaginal suppository), pellet, nasalpreparation, pulmonary preparation (inhalant), eye drop and the like,orally or parenterally (e.g., intravenous, intramuscular, subcutaneous,intraorgan, intranasal, intradermal, instillation, intracerebral,intrarectal, intravaginal, intraperitoneal and intratumoradministrations, administration to the vicinity of tumor, andadministration to the lesion).

The representative content of the compound of the present invention inthe medicament of the present invention is about 0.01 wt % to about 100wt %, of the whole medicament.

While the dose of the compound of the present invention varies dependingon the subject of administration, administration route, target disease,symptom and the like, a single dose is generally about 0.01 to 100 mg/kgbody weight, preferably 0.05 to 30 mg/kg body weight, more preferably0.1 to 10 mg/kg body weight, for oral administration to adult maculardegeneration patients, and the dose is desirably administered in 1 to 3times per day.

As the above-mentioned pharmacologically acceptable carrier, which maybe used for the production of the medicament of the present invention,various organic or inorganic carrier substances conventionally used as apreparation material can be mentioned. For example, excipient,lubricant, binder and disintegrant for solid preparations; solvent,solubilizing agents, suspending agent, isotonic agent, and buffer andsoothing agent for liquid preparations can be mentioned. Wherenecessary, conventional additives such as preservatives, antioxidants,colorants, sweetening agents, adsorbing agents, wetting agents and thelike can be used appropriately in suitable amounts.

As the excipient, for example, lactose, sucrose, D-mannitol, starch,corn starch, crystalline cellulose, light anhydrous silicic acid can bementioned.

As the lubricant, for example, magnesium stearate, calcium stearate,talc, colloidal silica can be mentioned.

As the binder, for example, crystalline cellulose, sucrose, D-mannitol,dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, starch, saccharose, gelatin, methylcellulose,carboxymethylcellulose sodium can be mentioned.

As the disintegrant, for example, starch, carboxymethylcellulose,carboxymethylcellulose calcium, carboxymethylstarch sodium,L-hydroxypropylcellulose can be mentioned.

As the solvent, for example, water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil can be mentioned.

As the solubilizing agents, for example, polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate can bementioned.

As the suspending agent, for example, surfactants such asstearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, glycerolmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like can be mentioned.

As the isotonic agent, for example, glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol can be mentioned.

As the buffer, for example, buffers such as phosphates, acetates,carbonates, citrates and the like, can be mentioned.

As the soothing agent, for example, benzyl alcohol can be mentioned.

As the preservatives, for example, paraoxybenzoates, chlorobutanol,benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid canbe mentioned.

As the antioxidant, for example, sulfites, ascorbic acid, α-tocopherolcan be mentioned.

As the colorant, for example, water-soluble edible tar pigments (e.g.,foodcolors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4and 5, Food Color Blue Nos. 1 and 2 and the like), water insoluble lakepigments (e.g., aluminum salt of the aforementioned water-soluble edibletar pigment and the like), natural pigments (e.g., β-carotene,chlorophil, ferric oxide red etc.) can be mentioned.

As the sweetening agent, for example, saccharin sodium, dipotassiumglycyrrhizinate, aspartame, stevia can be mentioned.

As the adsorbent, porous starch, calcium silicate (trade name: FloriteRE), magnesium aluminometasilicate (trade name: Neusilin), lightanhydrous silicic acid (trade name: Sylysia) can be mentioned.

As the wetting agent, propylene glycol monostearate, sorbitanmonooleate, diethylene glycol monolaurate, polyoxyethylene lauryl ethercan be mentioned.

When the present compound is used as an ointment, it is produced bymixing the present compound with a conventional ointment base at aconcentration of about 0.001 to 3% (W/W), preferably about 0.01 to 1%(W/W). The production of ointment preferably includes a step ofpowderizing the present compound or a step of sterilizing thepreparation. Ointment is administered 1 to 4 times per day according tothe condition of the patients.

As the ointment base, purified lanolin, white petrolatum, macrogol,Plastibase, liquid paraffin can be mentioned.

With the aim of enhancing the action of the compound of the presentinvention or decreasing the dose of the compound and the like, thecompound can be used in combination with medicaments such as therapeuticagents for diabetes, therapeutic agents for diabetic complications,therapeutic agents for hyperlipidemia, antihypertensive agents,antiobesity agents, diuretics, therapeutic agents for maculardegeneration, antioxidants, nitric oxide inducing agents, matrixmetalloproteinase (MMPs) inhibitors, anti-angiogenesis agents,chemotherapeutic agents, immunotherapeutic agents, antithromboticagents, therapeutic agents for osteoporosis, antidementia agents,erectile dysfunction improving agents, therapeutic agents forincontinence, frequent urination, therapeutic agents for dysuria and thelike (hereinafter to be abbreviated as combination drugs). Theseconcomitant drugs may be low-molecular compounds, or high-molecularproteins, polypeptides, antibodies, vaccines or the like.

The time of administration of the compound of the present invention andthat of the combination drug are not limited, and they may beadministered simultaneously or in a staggered manner to theadministration subject.

The administration form is not particularly limited, and the compound ofthe present invention and a concomitant drug only need to be combined.Examples of such administration mode include the following:

(1) administration of a single preparation obtained by simultaneouslyprocessing the compound of the present invention and the combinationdrug,(2) simultaneous administration of two kinds of preparations of thecompound of the present invention and the combination drug, which havebeen separately produced, by the same administration route,(3) administration of two kinds of preparations of the compound of thepresent invention and the combination drug, which have been separatelyproduced, by the same administration route in a staggered manner,(4) simultaneous administration of two kinds of preparations of thecompound of the present invention and the combination drug, which havebeen separately produced, by different administration routes,(5) administration of two kinds of preparations of the compound of thepresent invention and the combination drug, which have been separatelyproduced, by different administration routes in a staggered manner(e.g., administration in the order of the compound of the presentinvention and the combination drug, or in the reverse order).

The dose of the combination drug can be appropriately determined withthe clinically-used dose as the standard. In addition, the mixing ratioof compound of the present invention and the combination drug can beappropriately determined according to the administration subject,administration route, target disease, symptom, combination and the like.For example, when the administration subject is human, 0.01 to 100 partsby weight of the combination drug can be used per 1 part by weight ofthe compound of the present invention. The compound can be used incombination with a means for providing the patients with an additionalor synergistic effect, for example, use of extracorporeal rheopheresis,use of a transplantable compact telescope, laser photocoagulation ofdrusen, a microstimulation therapy and the like.

Examples of the above-mentioned “therapeutic agent for diabetes” includeinsulin preparations (e.g., animal insulin preparations extracted frompancreas of bovine or swine; human insulin preparations geneticallysynthesized using Escherichia coli or yeast; zinc insulin; protaminezinc insulin; fragment or derivative of insulin (e.g., INS-1), oralinsulin preparation), insulin sensitizers (e.g., pioglitazone or a saltthereof (preferably hydrochloride), rosiglitazone or a salt thereof(preferably maleate), Netoglitazone (MCC-555), Rivoglitazone (CS-011),FK-614, compound described in WO 01/38325, Tesaglitazar (AZ-242),Ragaglitazar (NN-622), Muraglitazar (BMS-298585), Edaglitazone(BM-13-1258), Metaglidasen (MBX-102), Naveglitazar (LY-519818), MX-6054,LY-510929, AMG131 (T-131) or a salt thereof, THR-0921), α-glucosidaseinhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), biguanides(e.g., phenformin, metformin, buformin or a salt thereof (e.g.,hydrochloride, fumarate, succinate)), insulin secretagogues[sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide,chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride,glipizide, glybuzole), repaglinide, nateglinide, mitiglinide or calciumsalt hydrate thereof], dipeptidyl peptidase IV inhibitors (e.g.,Vildagliptin (LAF237), P32/98, Sitagliptin (MK-431), alogliptin,Trelagliptin, P93/01, PT-100, Saxagliptin (BMS-477118), BI1356, GRC8200,MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, T-6666, TS-021,KRP-104), β3 agonists (e.g., AJ-9677), GPR40 agonist, GLP-1 receptoragonists [e.g., GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin-4)),BIM-51077, Aib(8,35)hGLP-1(7,37)NH2, CJC-1131], amylin agonists (e.g.,pramlintide), phosphotyrosine phosphatase inhibitors (e.g., sodiumvanadate), gluconeogenesis inhibitors (e.g., glycogen phosphorylaseinhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists),SGLUT (sodium-glucose cotransporter) inhibitors (e.g., T-1095,dapagliflozin, remogliflozin), 11-hydroxysteroid dehydrogenaseinhibitors (e.g., BVT-3498), adiponectin or agonist thereof, IKKinhibitors (e.g., AS-2868), leptin resistance improving drugs,somatostatin receptor agonists (e.g., compounds described in WO01/25228, WO 03/42204, WO 98/44921, WO 98/45285, WO 99/22735 etc.),glucokinase activators (e.g., Ro-28-1675), and ACC2 (acetyl-CoAcarboxylase 2) inhibitor.

Examples of the “therapeutic agents for diabetic complications” includealdose reductase inhibitors (e.g., Tolrestat, Epalrestat, zenarestat,Zopolrestat, minalrestat, Fidarestat, CT-112, ranirestat (AS-3201)),neurotrophic factors and increasing drugs thereof (e.g., NGF, NT-3,BDNF, neurotrophin production-secretion promoters described inWO01/14372 (e.g.,4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole)),PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g.,ALT946, pimagedine, N-phenacylthiazolium bromide (ALT766), EXO-226,Pyridorin, Pyridoxamine), active oxygen scavengers (e.g., thiocticacid), cerebral vasodilators (e.g., tiapuride, mexiletine), somatostatinreceptor agonists (BIM23190), and apoptosis signal regulating kinase-1(ASK-1) inhibitors.

Examples of the “hyperlipidemia therapeutic agent” include statincompounds as cholesterol synthesis inhibitors (e.g., cerivastatin,pravastatin, simvastatin, lovastatin, rosuvastatin, atorvastatin,fluvastatin, pitavastatin or salts thereof (e.g., sodium salt, etc.)etc.), squalene synthetase inhibitors or fibrate compounds withhypotriglyceride action (e.g., bezafibrate, clofibrate, simfibrate,clinofibrate, etc.), cholesterol absorption inhibitors (e.g., zetia),anion-exchange resins (e.g., cholestyramine), probucol, nicotinic drugs(e.g., nicomol, niceritrol), phytosterols (e.g., soysterol,γ-oryzanol)), fish oil preparations (e.g., EPA, DHA, omacor), PPARα-agonist, PPAR γ-agonist, PPAR δ-agonist, LXR agonist, FXR antagonist,FXR agonist, DGAT inhibitor, MGAT inhibitor, MTP inhibitor (e.g.,lomitapide), and nucleic acid drugs containing ApoB antisense (e.g.,mipomersen) or PCSK9 siRNA antisense oligonucleotide.

Examples of the antihypertensive agent include angiotensin convertingenzyme inhibitors (e.g., captopril, enalapril, delapril and the like),angiotensin II antagonists (e.g., candesartan cilexetil, candesartan,azilsartan, azilsartan medoxomil, losartan, losartan potassium,eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan,olmesartan medoxomil etc.), calcium antagonist (e.g., manidipine,nifedipine, amlodipine, efonidipine, nicardipine etc.), β-blocker (e.g.,propranolol, nadolol, timolol, nipradilol, bunitrolol, indenolol,Penbutolol, carteolol, carvedilol, pindolol, acebutolol, atenolol,bisoprolol, metoprolol, labetalol, amosulalol, arotinolol etc.), andclonidine.

Examples of the “antiobesity agent” include monoamine uptake inhibitors(e.g., phentermine, sibutramine, mazindol, fluoxetine, tesofensine),serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptorantagonists, histamine H3 receptor, GABA modulator (e.g., topiramate),neuropeptide Y antagonists (e.g., velneperit), cannabinoid receptorantagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelinreceptor antagonists, ghrelin acylation enzyme inhibitors, opioidreceptor antagonists (e.g., GSK-1521498), orexin receptor antagonists,melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenaseinhibitors (e.g., AZD-4017), pancreatic lipase inhibitors (e.g.,orlistat, cetilistat), P3 agonists (e.g., N-5984), diacylglycerolacyltransferase 1 (DGAT1) inhibitors, acetylCoA carboxylase (ACC)inhibitors, stearate CoA desaturase inhibitors, microsomal triglyceridetransfer protein inhibitors (e.g., R-256918), Na-glucose cotransporterinhibitors (e.g., JNJ-28431754, remogliflozin), NFK inhibitors (e.g.,HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605), phosphotyrosinephosphatase inhibitors (e.g., sodium vanadate, Trodusquemin), GPR119agonists (e.g., PSN-821), glucokinase activators (e.g., AZD-1656),leptin, leptin derivatives (e.g., metreleptin), CNTF (ciliaryneurotrophic factor), BDNF (brain-derived neurotrophic factor),cholecystokinin agonists, glucagon-like peptide-1 (GLP-1) preparations(e.g., animal GLP-1 preparations extracted from the pancreas of bovineor swine; human preparations genetically synthesized using Escherichiacoli or yeast; fragments or derivatives of GLP-1 (e.g., exenatide,liraglutide)), amylin preparations (e.g., pramlintide, AC-2307),neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36,obineptide, TM-30339, TM-30335), oxyntomodulin preparations: FGF21preparations (e.g., animal FGF21 preparations extracted from thepancreas of bovine or swine; human FGF21 preparations geneticallysynthesized using Escherichia coli or yeast; fragments or derivatives ofFGF21), and anorexigenic agents (e.g., P-57).

Examples of the “diuretics” include xanthine derivatives (e.g., sodiumsalicylate and theobromine, calcium salicylate and theobromine),thiazide preparations (e.g., ethiazide, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, poly5thiazide,methyclothiazide), antialdosterone preparations (e.g., spironolactone,eplerenone, triamterene), carbonate dehydratase inhibitors (e.g.,acetazolamide), chlorobenzenesulfonamide preparations (e.g.,chlortalidone, mefruside, indapamide), azosemide, isosorbide, etacrynicacid, piretanide, bumetanide, and furosemide.

Examples of the therapeutic agent for macular degeneration includefenretinide (4-hydroxy(phenyl)retinamide), compound described in WO2009/042444, negatively-charged phospholipid, particular mineral (e.g.,copper-containing mineral such as copper oxide and the like, andzinc-containing mineral such as zinc oxide and the like,selenium-containing compound).

Examples of the antioxidant include vitamin C, vitamin E, β-carotene andother carotenoid, coenzyme Q,4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (also known as Tempol),lutein, butylated hydroxytoluene, resveratrol, trolox analogue(PNU-83836-E), and bilberry extract.

Examples of the nitric oxide inducing agent include L-arginine,L-homoarginine and N-hydroxy-L-arginine (e.g., nitrosated L-arginine,nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine, nitrosylatedL-homoarginine), L-arginine precursor and/or physiologically acceptablesalt thereof (e.g., citrulline, ornithine, glutamine, lysine),polypeptide containing at least one of the above-mentioned amino acids,enzyme arginase inhibitor (e.g., N-hydroxy-L-arginine and2(S)-amino-6-boronohexanoic acid), and substrate for nitric oxide orclosely-related derivative thereof.

Examples of the matrix metalloproteinase (MMPs) inhibitor include tissueinhibitors of metalloproteinase (TIMPs) (e.g., TIMP-1, TIMP-2, TIMP-3,TIMP-4), α2-macroglobulin, tetracycline (e.g., tetracycline,minocycline, doxycycline), hydroxamate (e.g., batimastat, MARIMISTAT,TROCADE), chelating agent (e.g., EDTA, cysteine, acetylcysteine,D-penicillamine, gold salt), synthetic MMP fragment,succinylmercaptopurine, phosphoramidate, and hydroxamic acid(hydroxaminic acid).

Examples of the anti-angiogenesis agent or anti-VEGF agent includeRhufab V2 (Lucentis), tryptophanyl-tRNA synthetase (TrpRS), Eye 001(anti-VERG pegylated aptamer), squalamine, Retaane 15 mg (anecortaveacetate for depot suspended product; Alcon, Inc.), Combretastain A4prodrug (CA4P), Macugen, Mifeprex (mifepristone-ru486), sub-tenontriamcinolone acetonide, intravitreal crystalline triamcinoloneacetonide, prinomastat (AG3340), fluocinolone acetonide (includingfluocinolone intraocular implant), VEGFR inhibitor, and VEGF-trap.

Examples of the chemotherapeutic agents include alkylating agents (e.g.,cyclophosphamide, ifosfamide), metabolic antagonists (e.g.,methotrexate, 5-fluorouracil and derivative thereof), antitumorantibiotics (e.g., mitomycin, Adriamycin, etc.), plant-derived antitumoragents (e.g., vincristine, vindesine, Taxol), cisplatin, carboplatin,etoposide and the like. Of these, Furtulon or NeoFurtulon, which are5-fluorouracil derivatives, and the like are preferable.

Examples of the above-mentioned “immunotherapeutic agents” includemicroorganism or bacterial components (e.g., muramyl dipeptidederivatives, Picibanil, etc.), polysaccharides having immunitypotentiating activity (e.g., lentinan, schizophyllan, krestin, etc.),cytokines obtained by genetic engineering techniques (e.g., interferon,interleukin (IL), etc.), colony stimulating factors (e.g., granulocytecolony stimulating factor, erythropoietin, etc.) and the like, withpreference given to interleukins such as IL-1, IL-2, IL-12 and the like.

Examples of the antithrombotic agent include heparin (e.g., heparinsodium, heparin calcium, dalteparin sodium), warfarin (e.g., warfarinpotassium), anti-thrombin drug (e.g., aragatroban, dabigatran),thrombolytic agent (e.g., urokinase), tisokinase, alteplase, nateplase,monteplase, pamiteplase), platelet aggregation inhibitor (e.g.,ticlopidine hydrochloride, cilostazol), ethyl icosapentate, beraprostsodium, sarpogrelate hydrochloride, prasugrel, E5555, SHC530348), FXainhibitor (e.g.,1-(1-{(2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperidin-4-yl)tetrahydropyrimidin-2(1H)-one,rivaroxaban, apixaban, DU-156, YM150).

Examples of the “therapeutic agents for osteoporosis” includealfacalcidol, calcitriol, elcaltonin, calcitonin salmon, estriol,ipriflavone, pamidronate disodium, alendronate sodium hydrate, andincadronate disodium.

Examples of the “antidementia agent” include tacrine, donepezil,rivastigmine, and galanthamine.

Examples of the erectile dysfunction improving drug include apomorphine,sildenafil citrate.

Examples of the therapeutic agents for urinary incontinence orpollakiuria include flavoxate hydrochloride, oxybutynin hydrochloride,propiverine hydrochloride.

Examples of the therapeutic agents for dysuria include acetylcholineesterase inhibitors (e.g., distigmine).

In addition, examples of the combination drug includes drugs having acachexia-improving action-established in animal models and clinicalsituations, such as cyclooxygenase inhibitors (e.g., indomethacin),progesterone derivatives (e.g., megestrol acetate), glucosteroids (e.g.,dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, fatmetabolism improving agents (e.g., eicosapentanoic acid), growthhormones, IGF-1, or antibodies to a cachexia-inducing factor such asTNF-α, LIF, IL-6, oncostatin M.

Furthermore, examples of the combination drug includes nerveregeneration promoting drugs (e.g., Y-128, VX-853, prosaptide),antidepressant (e.g., desipramine, amitriptyline, imipramine),antiepileptic (e.g., lamotrigine), antiarrhythmic drugs (e.g.,mexiletine), acetylcholine receptor ligand (e.g., ABT-594), endothelinreceptor antagonist (e.g., ABT-627), monoamine uptake inhibitors (e.g.,tramadol), narcotic analgesics (e.g., morphine), GABA receptor agonist(e.g., gabapentin), α2 receptor agonist (e.g., clonidine), topicalanalgesic (e.g., capsaicin), antianxiety drug (e.g., benzodiazepine),dopamine agonist (e.g., apomorphine), midazolam, ketoconazole and thelike.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples.However, the examples do not limit the present invention and the presentinvention can be modified within the scope of the present invention.

The “room temperature” in the following Examples is generally about 10°C. to about 35° C. The ratio for a mixed solvent is, unless otherwisespecified, a volume mixing ratio and % means wt % unless otherwisespecified.

In silica gel column chromatography, the indication of NH means use ofaminopropylsilane-bonded silica gel and the indication of Diol means useof 3-(2,3-dihydroxypropoxy)propylsilane bond silica gel. In HPLC (highperformance liquid chromatography), the indication of C18 means use ofoctadecyl-bonded silica gel. The ratio of elution solvents is, unlessotherwise specified, a volume mixing ratio.

In the following Examples, the following abbreviations are used.

mp: melting pointMS: mass spectrumM: molar concentrationCDCl₃: deuterated chloroformDMSO: dimethyl sulfoxideDMSO-d₆: deuterated dimethyl sulfoxide¹H NMR: proton nuclear magnetic resonanceLC/MS: liquid chromatography mass spectrometerESI: electrospray ionizationAPCI: atmospheric pressure chemical ionizationDME: 1,2-dimethoxyethane

DMA: N,N-dimethylacetamide

HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphateHOBt: 1-hydroxybenzotriazoleTHF: tetrahydrofuran

DMF: N,N-dimethylformamide

TFA: trifluoroacetic acidLHMDS: hexamethyldisilazane lithiumn-: normals-: secondaryt-: tertiary

¹H NMR was measured by Fourier-transform type NMR. For the analysis,ACD/SpecManager (trade name) and the like were used. Very mild peaks ofprotons of hydroxyl group, amino group and the like are not described.

MS was measured by LC/MS. As the ionization method, ESI method, or APCImethod was used. The data indicates those found. Generally molecular ionpeak ([M+H]⁺, [M−H]⁻ and the like) is observed; however, when thecompound has a tert-butoxycarbonyl group, a peak after elimination of atert-butoxycarbonyl group or tert-butyl group may be observed as afragment ion. When the compound has a hydroxyl group, a peak afterelimination of H₂O may be observed as a fragment ion. In the case of asalt, a molecular ion peak or fragment ion peak of free form isgenerally observed.

The unit of sample concentration (c) in optical rotation ([α]_(D)) isg/100 mL.

The elemental analytical value (Anal.) shows Calculated value (Calcd)and Found value (Found).

Example 13-oxo-3-((3S)-3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)propanoicacid A) trimethyl(2,2,2-trifluoro-1-(2-methoxyphenyl)ethoxy)silane

To a mixture of 2-methoxybenzaldehyde (40 g) and DMF (400 mL) was addedpotassium carbonate (4 g) at room temperature andtrimethyl(trifluoromethyl)silane (50 g) at 0° C., and the mixture wasstirred at room temperature for 4 hr. After completion of the reaction,the reaction mixture was diluted with water and extracted with diethylether. The extract was washed with water and saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give the title compound (57 g).

¹H NMR (300 MHz, CDCl₃) δ 0.08 (9H, s), 3.85 (3H, s), 5.54 (1H, q, J=6.6Hz), 6.89 (1H, d, J=8.4 Hz), 7.00 (1H, t, J=7.5 Hz), 7.28-7.37 (1H, m),7.58 (1H, d, J=7.8 Hz).

B) 2,2,2-trifluoro-1-(2-methoxyphenyl)ethanol

To a mixture oftrimethyl(2,2,2-trifluoro-1-(2-methoxyphenyl)ethoxy)silane (16 g) andTHF (100 mL) was added 1 M tetrabutylammonium fluoride THF solution (67mL) at 0° C., and the mixture was stirred at room temperature for 5 hr.After completion of the reaction, the reaction mixture was quenched withwater and extracted with ethyl acetate. The extract was washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure to give the title compound(11 g).

¹H NMR (400 MHz, CDCl₃) δ 3.64 (1H, brs), 3.90 (3H, s), 5.28 (1H, d,J=6.0 Hz), 6.95 (1H, d, J=8.0 Hz), 7.02 (1H, t, J=8.4 Hz), 7.33-7.42(2H, m).

C) 2,2,2-trifluoro-1-(2-methoxyphenyl)ethanone

To a mixture of 2,2,2-trifluoro-1-(2-methoxyphenyl)ethanol (1 g) anddichloromethane (30 mL) were added DMSO (2 mL) and Dess-Martin reagent(2.05 g) at room temperature, and the mixture was stirred at 50° C. for1 hr. After completion of the reaction, the reaction mixture wasquenched with water, and filtered through celite. The filtrate wasextracted with dichloromethane, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give the titlecompound (0.5 g).

¹H NMR (400 MHz, CDCl₃) δ 3.92 (3H, s), 6.98-7.10 (2H, m), 7.56-7.63(1H, m), 7.68 (1H, d, J=7.6 Hz).

D) 1-methoxy-2-(3,3,3-trifluoroprop-1-en-2-yl)benzene

To a mixture of methyltriphenylphosphonium bromide (100 g) and THF (300mL) was added potassium tert-butoxide (36.3 g) at room temperature, andthe mixture was stirred for 0.5 hr. Then, a mixture of2,2,2-trifluoro-1-(2-methoxyphenyl)ethanone (44 g) and THF (200 mL) wasadded at room temperature, and the mixture was stirred at roomtemperature for 4 hr. After completion of the reaction, the reactionmixture was quenched with water and extracted with ethyl acetate. Theextract was washed with water and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (9 g).

¹H NMR (400 MHz, CDCl₃) δ 3.82 (3H, s), 5.64 (1H, s), 6.08 (1H, d, J=0.8Hz), 6.90-7.00 (2H, m), 7.22 (1H, d, J=7.6 Hz), 7.31-7.39 (1H, m).

E) 3-(2-methoxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole

To a mixture of 1-methyl-1-nitrosourea (135 g) and diethyl ether (300mL) was slowly added a mixture of potassium hydroxide (112 g) and water(250 mL) at −10° C. The ether layer of the reaction mixture was slowlyadded to a mixture of 1-methoxy-2-(3,3,3-trifluoroprop-1-en-2-yl)benzene(10 g) and diethyl ether (300 mL) at −10° C. The reaction mixture wasslowly heated to room temperature, and the mixture was stirred at roomtemperature for 16 hr. The solvent of the reaction mixture wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/petroleum ether) to givethe title compound (9.3 g).

MS: [M+H]⁺ 245.2.

F) 1-methoxy-2-(1-(trifluoromethyl)cyclopropyl)benzene

Xylene (50 mL) was added to3-(2-methoxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole (9.3 g),and the mixture was stirred at 140° C. for 3 hr. After completion of thereaction, the reaction mixture was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (6.4 g).

¹H NMR (400 MHz, CDCl₃) δ 0.95-1.03 (1H, m), 1.32-1.40 (2H, m), 3.85(3H, s), 6.85-7.03 (2H, m), 7.27-7.34 (1H, m), 7.35-7.42 (1H, m).

G) 2-(1-(trifluoromethyl)cyclopropyl)phenol

To a mixture of 1-methoxy-2-(1-(trifluoromethyl)cyclopropyl)benzene (6.4g) and dichloromethane (64 mL) was added boron tribromide (4.89 mL) at0° C., and the mixture was stirred at room temperature for 1 hr. Aftercompletion of the reaction, the reaction mixture was quenched with icewater and extracted with dichloromethane. The extract was washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/petroleum ether) togive the title compound (3.2 g).

¹H NMR (400 MHz, CDCl₃) δ 1.06 (2H, s), 1.44-1.51 (2H, m), 5.32 (1H, s),6.87-6.88 (2H, m), 7.21-7.29 (1H, m), 7.30-7.36 (1H, m).

H) (S)-tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate

To a mixture of (S)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate (48.5 g) and pyridine (200mL) was added 4-methylbenzene-1-sulfonyl chloride (50.5 g) at roomtemperature, and the mixture was stirred at room temperature overnight.The solvent of the reaction mixture was evaporated under reducedpressure, the residue was diluted with water, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure to give the title compound (78.4 g).

¹H NMR (300 MHz, CDCl₃) δ 1.44 (9H, s), 1.63-1.73 (1H, m), 1.95 (1H,brs), 2.40-2.64 (4H, m), 3.00 (1H, dd, J=11.1, 7.0 Hz), 3.21-3.54 (3H,m), 3.87-4.05 (2H, m), 7.36 (2H, d, J=8.3 Hz), 7.79 (2H, d, J=8.3 Hz).

I) (S)-tert-butyl3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of 2-(1-(trifluoromethyl)cyclopropyl)phenol (3.18 g) andDMF (50 mL) were added (S)-tert-butyl3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (5.6 g) and potassiumphosphate (5 g) at room temperature, and the mixture was stirred at 80°C. for 16 hr. The reaction mixture was diluted with water and extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/petroleum ether) to give thetitle compound (3.5 g).

MS: [M+H]⁺ 386.5.

J) (S)-3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidinehydrochloride

To a mixture of (S)-tert-butyl3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidine-1-carboxylate(3.5 g) and 1,4-dioxane (20 mL) was added 4N hydrochloricacid-1,4-dioxane (20 mL) at 0° C., and the mixture was stirred at roomtemperature for 4 hr. After completion of the reaction, the reactionmixture was concentrated under reduced pressure to give the titlecompound (2.92 g).

MS, found: 286.3.

K) (S)-ethyl3-oxo-3-(3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)propanoate

To a mixture of 3-ethoxy-3-oxopropanoic acid (1.2 g) and DMF (50 mL)were added(S)-3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidinehydrochloride (2.92 g), HATU (5.18 g) and N,N-diisopropylethylamine(4.75 mL) at room temperature, and the mixture was stirred at roomtemperature for 16 hr. After completion of the reaction, the reactionmixture was diluted with water and extracted with ethyl acetate. Theextract was washed with water and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (2.15 g).

MS: [M+H]⁺ 400.3.

L)3-oxo-3-((3S)-3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)propanoicacid

To a mixture of (S)-ethyl3-oxo-3-(3-((2-(1-(trifluoromethyl)cyclopropyl) phenoxy)methyl)pyrrolidin-1-yl)propanoate (1.1 g) and ethanol (10 mL) was added 1Naqueous lithium hydroxide solution (10.00 mL) at 0° C., and the mixturewas stirred at 0° C. for 1 hr. The reaction mixture was neutralized with1N hydrochloric acid (10 mL) at 0° C., diluted with ethyl acetate,poured into saturated brine, and the mixture was extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The obtained solid wasrecrystallized from ethyl acetate/heptane, washed with ethylacetate/heptane (=1/20) and heptane, and dried under reduced pressure togive the title compound (0.840 g).

¹H NMR (300 MHz, CDCl₃) δ 0.92-1.06 (2H, m), 1.31-1.43 (2H, m),1.84-2.40 (2H, m), 2.72-3.00 (1H, m), 3.28-3.38 (2H, m), 3.39-4.13 (6H,m), 6.84 (1H, d, J=8.3 Hz), 6.92-7.02 (1H, m), 7.27-7.35 (1H, m), 7.40(1H, d, J=7.2 Hz), 13.46-14.61 (1H, m).

Example 23-((3S)-3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid A) 1-bromo-2-(2-methylallyloxy)benzene

To a mixture of 2-bromophenol (100 g) and acetone (1000 mL) were addedpotassium carbonate (119 g) and 3-bromo-2-methylpropene (78 g) at roomtemperature, and the mixture was stirred at 60° C. for 15 hr. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure, diluted with ethyl acetate, and the mixture was washedwith water and saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/petroleumether) to give the title compound (112 g)

¹H NMR (400 MHz, CDCl₃) δ 1.86 (3H, s), 4.50 (2H, s), 4.83-5.22 (2H, m),6.79-6.86 (1H, m), 6.88 (1H, d, J=8.4 Hz), 7.20-7.30 (1H, m), 7.54 (1H,dd, J=7.6, 1.6 Hz).

B) 2-(1-methylcyclopropyl)phenol

To a mixture of 1-bromo-2-(2-methylallyloxy)benzene (10 g) and diethylether (200 mL) was added tert-butyllithium (59 mL, 88 mmol) at −78° C.,and the mixture was stirred at −78° C. for 0.5 hr. Then,N,N,N′,N′-tetramethylethylenediamine (10.2 g) was added at −78° C., andthe mixture was stirred at room temperature for 18 hr. After completionof the reaction, the reaction mixture was quenched with ice water at 0°C. and extracted with ethyl acetate. The extract was washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/petroleum ether) togive the title compound (2.8 g).

MS, found: 130.3.

C) (S)-tert-butyl3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of 2-(1-methylcyclopropyl)phenol (1 g) and DMF (25 mL) wereadded potassium phosphate (2.14 g) and (S)-tert-butyl3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (2.38 g) at roomtemperature, and the mixture was stirred at 80° C. overnight. Aftercompletion of the reaction, the reaction mixture was diluted with icewater and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/petroleum ether) to givethe title compound (1 g).

MS: [M+H]⁺ 332.4.

D) (S)-3-((2-(1-methylcyclopropyl) phenoxy)methyl)pyrrolidinehydrochloride

To a mixture of (S)-tert-butyl3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidine-1-carboxylate (1g) and 1,4-dioxane (5 mL) was added 4N hydrochloric acid-1,4-dioxane (5mL) at 0° C., and the mixture was stirred at room temperature for 18 hr.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure and the obtained solid was washed with diethylether to give the title compound (0.72 g).

MS, found: 232.2.

E) (S)-ethyl3-(3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of 3-ethoxy-3-oxopropanoic acid (0.28 g),(S)-3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidine hydrochloride(0.5 g) and DMF (5 mL) were added HATU (1.07 g) andN,N-diisopropylethylamine (0.727 g) at room temperature, and the mixturewas stirred at room temperature for 5 hr. After completion of thereaction, the reaction mixture was diluted with ice water and extractedwith ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution, 2N hydrochloric acid, water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to give the titlecompound (0.4 g).

MS: [M+H]⁺ 346.2.

F)3-((3S)-3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid

To a mixture of (S)-ethyl3-(3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate(3.340 g) and ethanol (33 mL) was added 1N aqueous lithium hydroxidesolution (12 mL) at 0° C., and the mixture was stirred at 0° C. for 2hr. The reaction mixture was concentrated, diluted with water,neutralized with 1N hydrochloric acid (12 mL) and extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The obtained solid was recrystallized from ethylacetate/hexane to give the title compound (2.935 g).

¹H NMR (300 MHz, CDCl₃) δ 0.64 (2H, q, J=4.2 Hz), 0.68-0.79 (2H, m),1.29 (3H, d, J=1.1 Hz), 1.89-2.42 (2H, m), 2.74-3.03 (1H, m), 3.30-3.40(2H, m), 3.44-4.15 (6H, m), 6.79 (1H, d, J=8.3 Hz), 6.85-6.96 (1H, m),7.11-7.22 (1H, m), 7.28 (1H, d, J=1.9 Hz), 14.13 (1H, brs).

Example 33-((3S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid A) 2-(1-hydroxycyclobutyl)phenol

To a mixture of 2-bromophenol (50 g) and diethyl ether (800 mL) wasslowly added dropwise n-butyllithium (397 mL, 1.6 M hexane solution) at−78° C., and the mixture was stirred at room temperature for 2.5 hr. Thereaction mixture was cooled to −78° C., cyclobutanone (30.3 g) was addedat −78° C., and the mixture was heated to room temperature, and stirredat room temperature for 18 hr. After completion of the reaction, thereaction mixture was quenched with saturated aqueous ammonium chloridesolution at 0° C. and extracted with ethyl acetate. The extract waswashed with water and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to give thetitle compound (55 g).

MS, found: 147.1.

B) 2-cyclobutylphenol

To a mixture of 2-(1-hydroxycyclobutyl)phenol (55 g) and dichloromethane(600 mL) was added triethylsilane (116.7 g) at 0° C., and the mixturewas stirred at 0° C. for 20 min. Then, TFA (100 mL) was added at 0° C.,and the mixture was stirred at room temperature for 18 hr. Aftercompletion of the reaction, the reaction mixture was diluted with waterand extracted with dichloromethane. The extract was washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/petroleum ether) togive the title compound (40 g).

MS: [M+H]⁺ 149.1.

C) (S)-tert-butyl3-((2-cyclobutylphenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of 2-cyclobutylphenol (1 g) and DMF (25 mL) were added(S)-tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (2.38 g)and potassium phosphate (2.14 g) at room temperature, and the mixturewas stirred at 80° C. overnight. After completion of the reaction, thereaction mixture was quenched with ice water and extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (1 g).

¹H NMR (300 MHz, CDCl₃) δ 1.47 (9H, s), 1.81 (2H, d, J=9.2 Hz),1.95-2.22 (4H, m), 2.24-2.38 (2H, m), 2.69 (1H, s), 3.22 (1H, dd,J=10.9, 7.2 Hz), 3.27-3.78 (4H, m), 3.90 (2H, qd, J=9.2, 6.8 Hz), 6.77(1H, d, J=8.1 Hz), 6.93 (1H, d, J=7.4 Hz), 7.08-7.31 (2H, m).

D) (S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidine hydrochloride

To a mixture of (S)-tert-butyl3-((2-cyclobutylphenoxy)methyl)pyrrolidine-1-carboxylate (1 g) and1,4-dioxane (5 mL) was added 4N hydrochloric acid-1,4-dioxane (5 mL) at0° C., and the mixture was stirred at room temperature for 18 hr. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The obtained solid was washed with diethyl ether togive the title compound (0.72 g).

MS, found: 232.3.

E) (S)-ethyl3-(3-((2-cyclobutylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of 3-ethoxy-3-oxopropanoic acid (0.25 g),(S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidine hydrochloride (0.503 g)and DMF (5 mL) were added HATU (1.07 g) and N,N-diisopropylethylamine(0.732 g) at room temperature, and the mixture was stirred at roomtemperature for 5 hr. After completion of the reaction, the reactionmixture was diluted with ice water and extracted with ethyl acetate. Theextract was washed with aqueous sodium hydrogen carbonate solution and2N hydrochloric acid, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure to give a residue.

To a mixture of 3-ethoxy-3-oxopropanoic acid (4.96 g),(S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidine hydrochloride (10 g) andDMF (200 mL) were added HATU (21.4 g) and N,N-diisopropylethylamine(14.54 g) at room temperature, and the mixture was stirred at roomtemperature for 5 hr. After completion of the reaction, the reactionmixture was diluted with ice water and extracted with ethyl acetate. Theextract was washed with aqueous sodium hydrogen carbonate solution and2N hydrochloric acid, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue wasmixed with the residue obtained earlier, and the mixture was purified bysilica gel column chromatography (ethyl acetate/petroleum ether) to givethe title compound (4 g).

MS: [M+H]⁺ 346.3.

F)3-((3S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid

To a mixture of (S)-ethyl3-(3-((2-cyclobutylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate(3.870 g) and ethanol (39 mL) was added 1N aqueous lithium hydroxidesolution (16 mL) at 0° C., and the mixture was stirred at 0° C. for 2hr. The reaction mixture was concentrated, diluted with water,neutralized with 1N hydrochloric acid and extracted with ethyl acetate.The extract was washed with saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theobtained solid was recrystallized from ethyl acetate/hexane to give thetitle compound (3.284 g).

¹H NMR (300 MHz, CDCl₃) δ 1.75-2.42 (8H, m), 2.69-2.98 (1H, m),3.30-4.11 (9H, m), 6.76 (1H, d, J=7.9 Hz), 6.92-7.02 (1H, m), 7.10-7.19(1H, m), 7.23 (1H, d, J=6.8 Hz), 14.10 (1H, brs).

Example 43-((3S)-3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid A) (S)-tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate

To a mixture of (S)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate (48.5 g) and pyridine (200mL) was added 4-methylbenzene-1-sulfonyl chloride (50.5 g) at roomtemperature, and the mixture was stirred at room temperature overnight.The solvent of the reaction mixture was evaporated under reducedpressure, and the residue was diluted with water and extracted withethyl acetate. The extract was washed with saturated brine, and driedover magnesium sulfate. The solvent was evaporated under reducedpressure to give the title compound (78.4 g).

¹H NMR (300 MHz, CDCl₃) δ 1.44 (9H, s), 1.63-1.73 (1H, m), 1.95 (1H,brs), 2.40-2.64 (4H, m), 3.00 (1H, dd, J=11.1, 7.0 Hz), 3.21-3.54 (3H,m), 3.87-4.05 (2H, m), 7.36 (2H, d, J=8.3 Hz), 7.79 (2H, d, J=8.3 Hz)

B) (S)-tert-butyl3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of (S)-tert-butyl3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (108 g),2-cyclopentylphenol (47 g) and DMF (350 mL) was added potassiumphosphate (98 g) at room temperature, and the mixture was stirred undera nitrogen atmosphere at 80° C. for 10 hr. The reaction mixture wasquenched with water at room temperature and extracted with ethylacetate. The extract was washed with water and saturated brine, anddried over magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (99 g).

¹H NMR (300 MHz, CDCl₃) δ 1.47 (9H, s), 1.50-2.18 (10H, m), 2.48-2.81(1H, m), 3.15-3.75 (5H, m), 3.83-4.03 (2H, m), 6.81 (1H, d, J=8.3 Hz),6.87-6.96 (1H, m), 7.09-7.18 (1H, m), 7.22 (1H, dd, J=7.6, 1.5 Hz).

C) (S)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine

To a mixture of (S)-tert-butyl3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate (99 g) andethyl acetate (500 mL) was added 4N hydrochloric acid-ethyl acetate (215mL) at room temperature, and the mixture was stirred at room temperatureovernight. The solvent of the reaction mixture was evaporated underreduced pressure, and the residue was neutralized with 1N aqueous sodiumhydroxide solution (500 mL) at 0° C. and extracted with ethyl acetate.The extract was washed with water and saturated brine, and dried overmagnesium sulfate. The solvent was evaporated under reduced pressure togive the title compound (63.1 g).

MS: [M+H]⁺ 246.1.

D) (S)-ethyl3-(3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of (S)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine (63.1g), 3-ethoxy-3-oxopropanoic acid (51.0 g), HOBt monohydrate (59.1 g),triethylamine (43.0 mL) and DMF (300 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (74.0 g) at0° C., and the mixture was stirred at room temperature overnight. Thereaction mixture was quenched with water at room temperature andextracted with ethyl acetate. The extract was washed with water andsaturated brine, and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (84.7 g).

MS: [M+H]⁺ 360.2.

E)3-((3S)-3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid

To a mixture of (S)-ethyl3-(3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate(1.186 g), THF (10 mL) and ethanol (10 mL) was added 2N aqueous lithiumhydroxide solution (3.30 mL) at 0° C., and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was neutralized with 1Nhydrochloric acid at 0° C. and extracted with ethyl acetate. The extractwas washed with water and saturated brine, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedsolid was recrystallized from ethyl acetate/hexane to give the titlecompound (1.040 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.43-2.20 (10H, m), 2.54-2.85 (1H, m),3.12-3.40 (5H, m), 3.41-3.76 (3H, m), 3.85-4.03 (2H, m), 6.75-6.98 (2H,m), 7.06-7.23 (2H, m), 12.66 (1H, brs).

Example 53-((3S)-3-((2-cyclohexylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid A) (S)-tert-butyl3-((2-cyclohexylphenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of (S)-tert-butyl3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (3.55 g) and DMF (30 mL)were added 2-cyclohexylphenol (1.763 g) and potassium phosphate (3.18 g)at room temperature, and the mixture was stirred at 80° C. overnight.The reaction mixture was diluted with water and extracted with ethylacetate. The extract was washed with water and saturated brine, anddried over magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (3.50 g).

MS, found: 345.3.

B) (S)-3-((2-cyclohexylphenoxy)methyl)pyrrolidine hydrochloride

A mixture of (S)-tert-butyl3-((2-cyclohexylphenoxy)methyl)pyrrolidine-1-carboxylate (3.49 g) and 4Nhydrochloric acid-ethyl acetate (20 mL) was stirred at room temperaturefor 1 hr. The solvent of the reaction mixture was evaporated underreduced pressure to give the title compound (2.87 g).

MS: [M+H]⁺ 260.3.

C) (S)-ethyl3-(3-((2-cyclohexylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of (S)-3-((2-cyclohexylphenoxy)methyl)pyrrolidinehydrochloride (2.87 g), 3-ethoxy-3-oxopropanoic acid (1.922 g), HOBtmonohydrate (2.228 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2.79 g) and DMF (20 mL) was added triethylamine (3.38 mL)at room temperature, and the mixture was stirred at room temperatureovernight. The reaction mixture was diluted with water and extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (2.500g).

MS: [M+H]⁺ 374.2.

D)3-((3S)-3-((2-cyclohexylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid

To a mixture of (S)-ethyl3-(3-((2-cyclohexylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate(2.465 g), THF (10 mL) and ethanol (10 mL) was added 2N aqueous lithiumhydroxide solution (6.60 mL) at 0° C., and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was neutralized with 1Nhydrochloric acid at 0° C. and extracted with ethyl acetate. The extractwas washed with water and saturated brine, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedsolid was recrystallized from ethyl acetate/hexane to give the titlecompound (1.600 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.11-1.51 (5H, m), 1.64-1.93 (6H, m),1.93-2.19 (1H, m), 2.55-2.97 (2H, m), 3.20 (1H, dd, J=12.1, 7.2 Hz),3.26-3.40 (5H, m), 3.42-3.77 (3H, m), 3.83-4.07 (2H, m), 6.82-6.98 (2H,m), 7.06-7.20 (2H, m), 12.54-12.77 (1H, m).

Example 63-((3R)-3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid A) (R)-tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate

To a mixture of (R)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate (2.013 g) and pyridine (15mL) was added 4-methylbenzene-1-sulfonyl chloride (2.097 g) at roomtemperature, and the mixture was stirred at room temperature overnight.The solvent of the reaction mixture was evaporated under reducedpressure, and the residue was diluted with water and extracted withethyl acetate. The extract was washed with saturated brine, and driedover magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (3.18 g).

MS, found: 300.0.

B) (R)-tert-butyl3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of (R)-tert-butyl3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (2.133 g) and DMF (20 mL)were added 2-cyclopentylphenol (0.973 g) and potassium phosphate (1.910g) at room temperature, and the mixture was stirred at 80° C. overnight.The reaction mixture was diluted with water and extracted with ethylacetate. The extract was washed with water and saturated brine, anddried over magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (1.850 g).

MS, found: 290.1.

C) (R)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine

To a mixture of (R)-tert-butyl3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate (1.831 g) andethyl acetate (5 mL) was added 4N hydrochloric acid-ethyl acetate (13.25mL) at room temperature, and the mixture was stirred at room temperaturefor 2 hr. The solvent of the reaction mixture was evaporated underreduced pressure, and the residue was diluted with 10% aqueous potassiumcarbonate solution (100 mL) and extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure to give thetitle compound (1.200 g).

MS: [M+H]⁺ 246.1.

D) (R)-ethyl3-(3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of (R)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine (1.202g), 3-ethoxy-3-oxopropanoic acid (0.777 g), HOBt monohydrate (1.126 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.409 g)and DMF (12 mL) was added triethylamine (1.707 mL) at room temperature,and the mixture was stirred at room temperature overnight. At roomtemperature, the reaction mixture was diluted with water and extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.180g).

MS: [M+H]⁺ 360.1.

E)3-((3R)-3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid

To a mixture of (R)-ethyl3-(3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate(1.150 g) and ethanol (10 mL) was added 2N aqueous lithium hydroxidesolution (3.20 mL) at room temperature, and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was neutralized with 2Nhydrochloric acid at 0° C. and extracted with ethyl acetate. The extractwas washed with water and saturated brine, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedsolid was recrystallized from ethyl acetate/heptane to give the titlecompound (0.930 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.43-1.84 (7H, m), 1.85-1.98 (2H, m),1.98-2.19 (1H, m), 2.56-2.83 (1H, m), 3.15-3.33 (3H, m), 3.39-3.75 (3H,m), 3.88-4.04 (2H, m), 6.83-6.96 (2H, m), 7.07-7.22 (2H, m), 12.66 (1H,brs).

Example 73-(3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoic acidA) tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate(4.03 g) and pyridine (30 mL) was added 4-methylbenzene-1-sulfonylchloride (4.19 g) at room temperature, and the mixture was stirred atroom temperature overnight. The solvent of the reaction mixture wasevaporated under reduced pressure, and the residue was diluted withwater and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (6.24 g).

MS, found: 300.0.

B) tert-butyl 3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate(2.133 g) and DMF (20 mL) were added 2-cyclopentylphenol (0.973 g) andpotassium phosphate (1.910 g) at room temperature, and the mixture wasstirred at 80° C. overnight. The reaction mixture was diluted with waterand extracted with ethyl acetate. The extract was washed with water andsaturated brine, and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (1.730 g).

MS, found: 290.1.

C) 3-((2-cyclopentylphenoxy)methyl)pyrrolidine

To a mixture of tert-butyl3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate (1.727 g) andethyl acetate (5 mL) was added 4N hydrochloric acid-ethyl acetate (12.50mL) at room temperature, and the mixture was stirred at room temperaturefor 2 hr. The solvent of the reaction mixture was evaporated underreduced pressure, and the residue was neutralized with 10% aqueouspotassium carbonate solution (100 mL) and extracted with ethyl acetate.The extract was washed with saturated brine, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure to give thetitle compound (1.210 g).

MS: [M+H]⁺ 246.1.

D) ethyl3-(3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of 3-((2-cyclopentylphenoxy)methyl)pyrrolidine (1.202 g),3-ethoxy-3-oxopropanoic acid (0.777 g), HOBt monohydrate (1.126 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.409 g)and DMF (12 mL) was added triethylamine (1.707 mL) at room temperature,and the mixture was stirred at room temperature overnight. At roomtemperature, the reaction mixture was diluted with water and extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.700g).

MS: [M+H]⁺ 360.2.

E) 3-(3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid

To a mixture of ethyl3-(3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate(1.186 g) and ethanol (17 mL) was added 2N aqueous lithium hydroxidesolution (3.30 mL) at room temperature, and the mixture was stirred atroom temperature for 1 hr. The reaction mixture was neutralized with 1Nhydrochloric acid at 0° C. and extracted with ethyl acetate. The extractwas washed with water and saturated brine, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedsolid was recrystallized from ethyl acetate/hexane to give the titlecompound (1.040 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.45-2.19 (10H, m), 2.56-2.81 (1H, m),3.14-3.40 (5H, m), 3.41-3.75 (3H, m), 3.88-4.03 (2H, m), 6.82-6.97 (2H,m), 7.08-7.23 (2H, m), 12.66 (1H, s).

Example 8 ethyl3-oxo-3-((3S)-3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)propanoateA) trimethyl(2,2,2-trifluoro-1-(2-methoxyphenyl)ethoxy)silane

To a mixture of 2-methoxybenzaldehyde (40 g) and DMF (400 mL) were addedpotassium carbonate (4 g) at room temperature andtrimethyl(trifluoromethyl)silane (50 g) at 0° C., and the mixture wasstirred at room temperature for 4 hr. After completion of the reaction,the reaction mixture was diluted with water and extracted with diethylether. The extract was washed with water and saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give the title compound (57 g).

¹H NMR (300 MHz, CDCl₃) δ 0.08 (9H, s), 3.85 (3H, s), 5.54 (1H, q, J=6.6Hz), 6.89 (1H, d, J=8.4 Hz), 7.00 (1H, t, J=7.5 Hz), 7.28-7.37 (1H, m),7.58 (1H, d, J=7.8 Hz).

B) 2,2,2-trifluoro-1-(2-methoxyphenyl)ethanol

To a mixture oftrimethyl(2,2,2-trifluoro-1-(2-methoxyphenyl)ethoxy)silane (16 g) andTHE (100 mL) was added 1 M tetrabutylammonium fluoride THF solution (67mL) at 0° C., and the mixture was stirred at room temperature for 5 hr.After completion of the reaction, the reaction mixture was quenched withwater and extracted with ethyl acetate. The extract was washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure to give the title compound(11 g).

¹H NMR (400 MHz, CDCl₃) δ 3.64 (1H, brs), 3.90 (3H, s), 5.28 (1H, d,J=6.0 Hz), 6.95 (1H, d, J=8.0 Hz), 7.02 (1H, t, J=8.4 Hz), 7.33-7.42(2H, m).

C) 2,2,2-trifluoro-1-(2-methoxyphenyl)ethanone

To a mixture of 2,2,2-trifluoro-1-(2-methoxyphenyl)ethanol (1 g) anddichloromethane (30 mL) were added DMSO (2 mL) and Dess-Martin reagent(2.05 g) at room temperature, and the mixture was stirred at 50° C. for1 hr. After completion of the reaction, the reaction mixture wasquenched with water, and filtered through celite. The filtrate wasextracted with dichloromethane, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give the titlecompound (0.5 g).

¹H NMR (400 MHz, CDCl₃) δ 3.92 (3H, s), 6.98-7.10 (2H, m), 7.56-7.63(1H, m), 7.68 (1H, d, J=7.6 Hz).

D) 1-methoxy-2-(3,3,3-trifluoroprop-1-en-2-yl)benzene

To a mixture of methyltriphenylphosphonium bromide (100 g) and THF (300mL) was added potassium tert-butoxide (36.3 g) at room temperature, andthe mixture was stirred for 0.5 hr. Then, a mixture of2,2,2-trifluoro-1-(2-methoxyphenyl)ethanone (44 g) and THF (200 mL) wasadded at room temperature, and the mixture was stirred at roomtemperature for 4 hr. After completion of the reaction, the reactionmixture was quenched with water and extracted with ethyl acetate. Theextract was washed with water and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (9 g).

¹H NMR (400 MHz, CDCl₃) δ 3.82 (3H, s), 5.64 (1H, s), 6.08 (1H, d, J=0.8Hz), 6.90-7.00 (2H, m), 7.22 (1H, d, J=7.6 Hz), 7.31-7.39 (1H, m).

E) 3-(2-methoxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole

To a mixture of 1-methyl-1-nitrosourea (135 g) and diethyl ether (300mL) was slowly added a mixture of potassium hydroxide (112 g) and water(250 mL) at −10° C. The ether layer of the reaction mixture was slowlyadded to a mixture of 1-methoxy-2-(3,3,3-trifluoroprop-1-en-2-yl)benzene(10 g) and diethyl ether (300 mL) at −10° C. The reaction mixture wasslowly heated to room temperature, and stirred at room temperature for16 hr. The solvent of the reaction mixture was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to give the titlecompound (9.3 g).

MS: [M+H]⁺ 245.2.

F) 1-methoxy-2-(1-(trifluoromethyl)cyclopropyl)benzene

To 3-(2-methoxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole (9.3g) was added xylene (50 mL), and the mixture was stirred at 140° C. for3 hr. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/petroleum ether) to givethe title compound (6.4 g).

¹H NMR (400 MHz, CDCl₃) δ 0.95-1.03 (1H, m), 1.32-1.40 (2H, m), 3.85(3H, s), 6.85-7.03 (2H, m), 7.27-7.34 (1H, m), 7.35-7.42 (1H, m).

G) 2-(1-(trifluoromethyl)cyclopropyl)phenol

To a mixture of 1-methoxy-2-(1-(trifluoromethyl)cyclopropyl)benzene (6.4g) and dichloromethane (64 mL) was added boron tribromide (4.89 mL) at0° C., and the mixture was stirred at room temperature for 1 hr. Aftercompletion of the reaction, the reaction mixture was quenched with icewater and extracted with dichloromethane. The extract was washed withwater and saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/petroleum ether) togive the title compound (3.2 g).

¹H NMR (400 MHz, CDCl₃) δ 1.06 (2H, s), 1.44-1.51 (2H, m), 5.32 (1H, s),6.87-6.88 (2H, m), 7.21-7.29 (1H, m), 7.30-7.36 (1H, m).

H) tert-butyl (3S)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (48.5 g) and pyridine(200 mL) was added 4-methylbenzene-1-sulfonyl chloride (50.5 g) at roomtemperature, and the mixture was stirred at room temperature overnight.The solvent of the reaction mixture was evaporated under reducedpressure, and the residue was diluted with water and extracted withethyl acetate. The extract was washed with saturated brine, and driedover magnesium sulfate. The solvent was evaporated under reducedpressure to give the title compound (78.4 g).

¹H NMR (300 MHz, CDCl₃) δ 1.44 (9H, s), 1.63-1.73 (1H, m), 1.95 (1H,brs), 2.40-2.64 (4H, m), 3.00 (1H, dd, J=11.1, 7.0 Hz), 3.21-3.54 (3H,m), 3.87-4.05 (2H, m), 7.36 (2H, d, J=8.3 Hz), 7.79 (2H, d, J=8.3 Hz).

I) tert-butyl(3S)-3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of 2-(1-(trifluoromethyl)cyclopropyl)phenol (3.18 g) andDMF (50 mL) were added tert-butyl(3S)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (5.6 g) and potassiumphosphate (5 g) at room temperature, and the mixture was stirred at 80°C. for 16 hr. The reaction mixture was diluted with water and extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/petroleum ether) to give thetitle compound (3.5 g).

MS: [M+H]⁺ 386.5.

J) (3S)-3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidinehydrochloride

To a mixture of tert-butyl(3S)-3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidine-1-carboxylate(3.5 g) and 1,4-dioxane (20 mL) was added 4N hydrochloricacid-1,4-dioxane (20 mL) at 0° C., and the mixture was stirred at roomtemperature for 4 hr. After completion of the reaction, the reactionmixture was concentrated under reduced pressure to give the titlecompound (2.92 g).

MS, found: 286.3.

K) ethyl3-oxo-3-((3S)-3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)propanoate

To a mixture of 3-ethoxy-3-oxopropanoic acid (1.2 g) and DMF (50 mL)were added(3S)-3-((2-(1-(trifluoromethyl)cyclopropyl)phenoxy)methyl)pyrrolidinehydrochloride (2.92 g), HATU (5.18 g) and N,N-diisopropylethylamine(4.75 mL) at room temperature, and the mixture was stirred at roomtemperature for 16 hr. After completion of the reaction, the reactionmixture was diluted with water and extracted with ethyl acetate. Theextract was washed with water and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (2.15 g).

MS: [M+H]⁺ 400.3.

Example 9 ethyl3-((3S)-3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoateA) 1-bromo-2-(2-methylallyloxy)benzene

To a mixture of 2-bromophenol (100 g) and acetone (1000 mL) were addedpotassium carbonate (119 g) and 3-bromo-2-methylpropene (78 g) at roomtemperature, and the mixture was stirred at 60° C. for 15 hr. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure, diluted with ethyl acetate, washed with water andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/petroleum ether) to givethe title compound (112 g).

¹H NMR (400 MHz, CDCl₃) δ 1.86 (3H, s), 4.50 (2H, s), 4.83-5.22 (2H, m),6.79-6.86 (1H, m), 6.88 (1H, d, J=8.4 Hz), 7.20-7.30 (1H, m), 7.54 (1H,dd, J=7.6, 1.6 Hz).

B) 2-(1-methylcyclopropyl)phenol

To a mixture of 1-bromo-2-(2-methylallyloxy)benzene (10 g) and diethylether (200 mL) was added tert-butyllithium (59 mL, 88 mmol) at −78° C.,and the mixture was stirred at −78° C. for 0.5 hr. Then,N,N,N′,N′-tetramethylethylenediamine (10.2 g) was added at −78° C., andthe mixture was stirred at room temperature for 18 hr. After completionof the reaction, the reaction mixture was quenched with ice water at 0°C. and extracted with ethyl acetate. The extract was washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/petroleum ether) togive the title compound (2.8 g).

MS, found: 130.3.

C) tert-butyl(3S)-3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of 2-(1-methylcyclopropyl)phenol (1 g) and DMF (25 mL) wereadded potassium phosphate (2.14 g) and tert-butyl(3S)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (2.38 g) at roomtemperature, and the mixture was stirred at 80° C. overnight. Aftercompletion of the reaction, the reaction mixture was diluted with icewater and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/petroleum ether) to givethe title compound (1 g).

MS: [M+H]⁺ 332.4.

D) (3S)-3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidinehydrochloride

To a mixture of tert-butyl(3S)-3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidine-1-carboxylate(1 g) and 1,4-dioxane (5 mL) was added 4N hydrochloric acid-1,4-dioxane(5 mL) at 0° C., and the mixture was stirred at room temperature for 18hr. After completion of the reaction, the reaction mixture wasconcentrated under reduced pressure. The obtained solid was washed withdiethyl ether to give the title compound (0.72 g).

MS, found: 232.2.

E) ethyl3-((3S)-3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of 3-ethoxy-3-oxopropanoic acid (0.28 g),(3S)-3-((2-(1-methylcyclopropyl)phenoxy)methyl)pyrrolidine hydrochloride(0.5 g) and DMF (5 mL) were added HATU (1.07 g) andN,N-diisopropylethylamine (0.727 g) at room temperature, and the mixturewas stirred at room temperature for 5 hr. After completion of thereaction, the reaction mixture was diluted with ice water and extractedwith ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution, 2N hydrochloric acid, water and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to give the titlecompound (0.4 g).

MS: [M+H]⁺ 346.2.

Example 10 ethyl3-((3S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoateA) 2-(1-hydroxycyclobutyl)phenol

To a mixture of 2-bromophenol (50 g) and diethyl ether (800 mL) wasslowly added dropwise n-butyllithium (397 mL, 1.6 M hexane solution) at−78° C., and the mixture was stirred at room temperature for 2.5 hr. Thereaction mixture was cooled to −78° C., cyclobutanone (30.3 g) was addedat −78° C., and the mixture was heated to room temperature and stirredat room temperature for 18 hr. After completion of the reaction, thereaction mixture was quenched with saturated aqueous ammonium chloridesolution at 0° C. and extracted with ethyl acetate. The extract waswashed with water and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to give thetitle compound (55 g).

MS, found: 147.1.

B) 2-cyclobutylphenol

To a mixture of 2-(1-hydroxycyclobutyl)phenol (55 g) and dichloromethane(600 mL) was added triethylsilane (116.7 g) at 0° C., and the mixturewas stirred at 0° C. for 20 min. Then, TFA (100 mL) was added at 0° C.,and the mixture was stirred at room temperature for 18 hr. Aftercompletion of the reaction, the reaction mixture was diluted with waterand extracted with dichloromethane. The extract was washed with waterand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/petroleum ether) togive the title compound (40 g).

MS: [M+H]⁺ 149.1.

C) tert-butyl(3S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of 2-cyclobutylphenol (1 g) and DMF (25 mL) were addedtert-butyl (3S)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (2.38 g)and potassium phosphate (2.14 g) at room temperature, and the mixturewas stirred at 80° C. overnight. After completion of the reaction, thereaction mixture was quenched with ice water and extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (1 g).

¹H NMR (300 MHz, CDCl₃) δ 1.47 (9H, s), 1.81 (2H, d, J=9.2 Hz),1.95-2.22 (4H, m), 2.24-2.38 (2H, m), 2.69 (1H, s), 3.22 (1H, dd,J=10.9, 7.2 Hz), 3.27-3.78 (4H, m), 3.90 (2H, qd, J=9.2, 6.8 Hz), 6.77(1H, d, J=8.1 Hz), 6.93 (1H, d, J=7.4 Hz), 7.08-7.31 (2H, m).

D) (3S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidine hydrochloride

To a mixture of tert-butyl(3S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidine-1-carboxylate (1 g) and1,4-dioxane (5 mL) was added 4N hydrochloric acid-1,4-dioxane (5 mL) at0° C., and the mixture was stirred at room temperature for 18 hr. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The obtained solid was washed with diethyl ether togive the title compound (0.72 g).

MS, found: 232.3.

E) ethyl3-((3S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of 3-ethoxy-3-oxopropanoic acid (0.25 g),(3S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidine hydrochloride (0.503 g)and DMF (5 mL) were added HATU (1.07 g) and N,N-diisopropylethylamine(0.732 g) at room temperature, and the mixture was stirred at roomtemperature for 5 hr. After completion of the reaction, the reactionmixture was diluted with ice water and extracted with ethyl acetate. Theextract was washed with aqueous sodium hydrogen carbonate solution and2N hydrochloric acid, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure to give a residue.

To a mixture of 3-ethoxy-3-oxopropanoic acid (4.96 g),(3S)-3-((2-cyclobutylphenoxy)methyl)pyrrolidine hydrochloride (10 g) andDMF (200 mL) were added HATU (21.4 g) and N,N-diisopropylethylamine(14.54 g) at room temperature, and the mixture was stirred at roomtemperature for 5 hr. After completion of the reaction, the reactionmixture was diluted with ice water and extracted with ethyl acetate. Theextract was washed with aqueous sodium hydrogen carbonate solution and2N hydrochloric acid, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue wasmixed with the residue obtained earlier, and the mixture was purified bysilica gel column chromatography (ethyl acetate/petroleum ether) to givethe title compound (4 g).

MS: [M+H]⁺ 346.3.

Example 11 ethyl3-((3S)-3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoateA) tert-butyl (3S)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (48.5 g) and pyridine(200 mL) was added 4-methylbenzene-1-sulfonyl chloride (50.5 g) at roomtemperature, and the mixture was stirred at room temperature overnight.The solvent of the reaction mixture was evaporated under reducedpressure, and the residue was diluted with water and extracted withethyl acetate. The extract was washed with saturated brine, and driedover magnesium sulfate. The solvent was evaporated under reducedpressure to give the title compound (78.4 g).

¹H NMR (300 MHz, CDCl₃) δ 1.44 (9H, s), 1.63-1.73 (1H, m), 1.95 (1H,brs), 2.40-2.64 (4H, m), 3.00 (1H, dd, J=11.1, 7.0 Hz), 3.21-3.54 (3H,m), 3.87-4.05 (2H, m), 7.36 (2H, d, J=8.3 Hz), 7.79 (2H, d, J=8.3 Hz).

B) tert-butyl(3S)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(3S)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (108 g),2-cyclopentylphenol (47 g) and DMF (350 mL) was added potassiumphosphate (98 g) at room temperature, and the mixture was stirred undera nitrogen atmosphere at 80° C. for 10 hr. At room temperature, thereaction mixture was quenched with water and extracted with ethylacetate. The extract was washed with water and saturated brine, anddried over magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (99 g).

¹H NMR (300 MHz, CDCl₃) δ 1.47 (9H, s), 1.50-2.18 (10H, m), 2.48-2.81(1H, m), 3.15-3.75 (5H, m), 3.83-4.03 (2H, m), 6.81 (1H, d, J=8.3 Hz),6.87-6.96 (1H, m), 7.09-7.18 (1H, m), 7.22 (1H, dd, J=7.6, 1.5 Hz)

C) (3S)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine

To a mixture of tert-butyl(3S)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate (99 g)and ethyl acetate (500 mL) was added 4N hydrochloric acid-ethyl acetate(215 mL) at room temperature, and the mixture was stirred at roomtemperature overnight. The solvent of the reaction mixture wasevaporated under reduced pressure, and the residue was neutralized with1N sodium hydroxide (500 mL) at 0° C., and extracted with ethyl acetate.The extract was washed with water and saturated brine, and dried overmagnesium sulfate. The solvent was evaporated under reduced pressure togive the title compound (63.1 g).

MS: [M+H]⁺ 246.1.

D) ethyl3-((3S)-3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of (3S)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine (63.1g), 3-ethoxy-3-oxopropanoic acid (51.0 g), HOBt monohydrate (59.1 g),triethylamine (43.0 mL) and DMF (300 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (74.0 g) at0° C., and the mixture was stirred at room temperature overnight. Thereaction mixture was quenched with water at room temperature andextracted with ethyl acetate. The extract was washed with water andsaturated brine, and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (84.7 g).

MS: [M+H]⁺ 360.2.

Example 12 ethyl3-((3S)-3-((2-cyclohexylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoateA) tert-butyl(3S)-3-((2-cyclohexylphenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(3S)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (3.55 g) and DMF (30mL) were added 2-cyclohexylphenol (1.763 g) and potassium phosphate(3.18 g) at room temperature, and the mixture was stirred at 80° C.overnight. The reaction mixture was diluted with water and extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (3.50g).

MS, found: 345.3.

B) (3S)-3-((2-cyclohexylphenoxy)methyl)pyrrolidine hydrochloride

A mixture of tert-butyl(3S)-3-((2-cyclohexylphenoxy)methyl)pyrrolidine-1-carboxylate (3.49 g)and 4N hydrochloric acid-ethyl acetate (20 mL) was stirred at roomtemperature for 1 hr. The solvent of the reaction mixture was evaporatedunder reduced pressure to give the title compound (2.87 g).

MS: [M+H]⁺ 260.3.

C) ethyl3-((3S)-3-((2-cyclohexylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of (3S)-3-((2-cyclohexylphenoxy)methyl)pyrrolidinehydrochloride (2.87 g), 3-ethoxy-3-oxopropanoic acid (1.922 g), HOBtmonohydrate (2.228 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2.79 g) and DMF (20 mL) was added triethylamine (3.38 mL)at room temperature, and the mixture was stirred at room temperatureovernight. The reaction mixture was diluted with water and extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (2.500g).

MS: [M+H]⁺ 374.2.

Example 13 ethyl3-((3R)-3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoateA) tert-butyl (3R)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (2.013 g) and pyridine(15 mL) was added 4-methylbenzene-1-sulfonyl chloride (2.097 g) at roomtemperature, and the mixture was stirred at room temperature overnight.The solvent of the reaction mixture was evaporated under reducedpressure, and the residue was diluted with water and extracted withethyl acetate. The extract was washed with saturated brine, and driedover magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (3.18 g).

MS, found: 300.0.

B) tert-butyl(3R)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl(3R)-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (2.133 g) and DMF (20mL) were added 2-cyclopentylphenol (0.973 g) and potassium phosphate(1.910 g) at room temperature, and the mixture was stirred at 80° C.overnight. The reaction mixture was diluted with water and extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.850g).

MS, found: 290.1.

C) (3R)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine

To a mixture of tert-butyl(3R)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate (1.831 g)and ethyl acetate (5 mL) was added 4N hydrochloric acid-ethyl acetate(13.25 mL) at room temperature, and the mixture was stirred at roomtemperature for 2 hr. The solvent of the reaction mixture was evaporatedunder reduced pressure, and the residue was diluted with 10% aqueouspotassium carbonate solution (100 mL) and extracted with ethyl acetate.The extract was washed with saturated brine, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure to give thetitle compound (1.200 g).

MS: [M+H]⁺ 246.1.

D) ethyl3-((3R)-3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of (3R)-3-((2-cyclopentylphenoxy)methyl)pyrrolidine (1.202g), 3-ethoxy-3-oxopropanoic acid (0.777 g), HOBt monohydrate (1.126 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.409 g)and DMF (12 mL) was added triethylamine (1.707 mL) at room temperature,and the mixture was stirred at room temperature overnight. At roomtemperature, the reaction mixture was diluted with water and extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.180g).

MS: [M+H]⁺ 360.1.

Example 14 ethyl3-(3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate A)tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate(4.03 g) and pyridine (30 mL) was added 4-methylbenzene-1-sulfonylchloride (4.19 g) at room temperature, and the mixture was stirred atroom temperature overnight. The solvent of the reaction mixture wasevaporated under reduced pressure, and the residue was diluted withwater and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (6.24 g).

MS, found: 300.0.

B) tert-butyl 3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate(2.133 g) and DMF (20 mL) were added 2-cyclopentylphenol (0.973 g) andpotassium phosphate (1.910 g) at room temperature, and the mixture wasstirred at 800° C. overnight. The reaction mixture was diluted withwater and extracted with ethyl acetate. The extract was washed withwater and saturated brine, and dried over magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (1.730 g).

MS, found: 290.1.

C) 3-((2-cyclopentylphenoxy)methyl)pyrrolidine

To a mixture of tert-butyl3-((2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate (1.727 g) andethyl acetate (5 mL) was added 4N hydrochloric acid-ethyl acetate (12.50mL) at room temperature, and the mixture was stirred at room temperaturefor 2 hr. The solvent of the reaction mixture was evaporated underreduced pressure, and the residue was neutralized with 10% aqueouspotassium carbonate solution (100 mL) and extracted with ethyl acetate.The extract was washed with saturated brine, and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure to give thetitle compound (1.210 g).

MS: [M+H]⁺ 246.1.

D) ethyl3-(3-((2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of 3-((2-cyclopentylphenoxy)methyl)pyrrolidine (1.202 g),3-ethoxy-3-oxopropanoic acid (0.777 g), HOBt monohydrate (1.126 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.409 g)and DMF (12 mL) was added triethylamine (1.707 mL) at room temperature,and the mixture was stirred at room temperature overnight. At roomtemperature, the reaction mixture was diluted with water and extractedwith ethyl acetate. The extract was washed with water and saturatedbrine, and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.700g).

MS: [M+H]⁺ 360.2.

Example 15 methyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2,2-difluoro-3-oxopropanoateA) 1-(5-fluoro-2-methoxyphenyl)cyclopentanol

To a mixture of 2-bromo-4-fluoro-1-methoxybenzene (20 g) and diethylether (200 mL) was added n-butyllithium (2.6 M THF solution, 74.5 mL) at−78° C., and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was cooled to −78° C., cyclopentanone (10.6 g) wasadded, and the mixture was stirred at room temperature for 10 hr. Thereaction mixture was cooled to 0° C., quenched with saturated aqueousammonium chloride solution and extracted with ethyl acetate. The extractwas dried over anhydrous sodium sulfate and the solvent was evaporatedunder reduced pressure to give the title compound (22 g).

¹H NMR (400 MHz, CDCl₃) δ 1.46-1.55 (2H, m), 1.65-1.82 (4H, m),1.97-2.05 (2H, m), 3.30 (1H, quin, J=8.4 Hz), 3.79 (3H, s), 6.73-6.76(1H, m), 6.78-6.84 (1H, m), 6.92 (1H, dd, J=10.0, 3.2 Hz).

B) 2-cyclopentyl-4-fluoro-1-methoxybenzene

To a mixture of 1-(5-fluoro-2-methoxyphenyl)cyclopentanol (22 g) anddichloromethane (150 mL) were added triethylsilane (30 g) andtrifluoroacetic acid (30 mL) at 0° C., and the mixture was stirred atroom temperature for 10 hr. The reaction mixture was quenched withsaturated aqueous sodium hydrogen carbonate solution and extracted withdichloromethane. The extract was dried over anhydrous sodium sulfate andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (14.2 g).

¹H NMR (400 MHz, CDCl₃) δ 1.45-1.55 (2H, m), 1.64-1.82 (4H, m),1.97-2.04 (2H, m), 3.30 (1H, quin, J=8.4 Hz), 3.79 (3H, s), 6.73-6.76(1H, m), 6.78-6.83 (1H, m), 6.92 (1H, dd, J=10.0, 3.2 Hz).

C) 2-cyclopentyl-4-fluorophenol

To a mixture of 2-cyclopentyl-4-fluoro-1-methoxybenzene (14 g) anddichloromethane (75 mL) was added boron tribromide (21.6 g) at −78° C.,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was poured into ice-cooled water and extracted withdichloromethane. The extract was dried over anhydrous sodium sulfate andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (12 g).

¹H NMR (300 MHz, CDCl₃) δ 1.53-1.87 (6H, m), 2.00-2.10 (2H, m), 3.18(1H, quin, J=8.3 Hz), 4.60 (1H, brs), 6.66-6.78 (2H, m), 6.90 (1H, dd,J=10.1, 2.7 Hz).

D) tert-butyl3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate(9.8 g), 2-cyclopentyl-4-fluorophenol (6 g) and DMF (100 mL) was addedpotassium phosphate (17.5 g) at 0° C., and the mixture was stirred at80° C. for 10 hr. The reaction mixture was poured into ice-cooled waterand extracted with ethyl acetate. The extract was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (7 g).

MS: [M+H]⁺ 364.2.

E) 3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidine hydrochloride

To a mixture of tert-butyl3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidine-1-carboxylate (7 g)and 1,4-dioxane (15 mL) was added 4N hydrochloric acid-1,4-dioxane (35mL) at 0° C., and the mixture was stirred at room temperature for 4 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was washed with n-pentane to give the title compound (5 g).

MS: [M−HCl+H]⁺ 264.1.

F) methyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2,2-difluoro-3-oxopropanoate

To a mixture of 3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidinehydrochloride (800 mg), dimethyl difluoromalonate (615 mg) and1,4-dioxane (5 mL) was added trimethylaluminum (1 M toluene solution,3.14 mL) at 0° C., and the mixture was stirred at 70° C. for 10 hr. Thereaction mixture was quenched with saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The extract was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (500 mg).

MS: [M+H]⁺ 400.3.

Example 16 G)3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2,2-difluoro-3-oxopropanoicacid

To a mixture of methyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2,2-difluoro-3-oxopropanoate(500 mg), THF (8 mL) and water (4 mL) was added sodium hydroxide (207mg) at 0° C., and the mixture was stirred at room temperature for 5 hr.The reaction mixture was acidified with 1N hydrochloric acid andextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The residue was washed with n-pentane and purified by HPLC (C18, mobilephase: water/acetonitrile (1% trifluoroacetic acid-containing system))to give the title compound (55 mg).

¹H NMR (400 MHz, MeOD) δ 1.53-1.55 (2H, m), 1.68-1.85 (5H, m), 1.91-2.07(3H, m), 2.15-2.25 (1H, m), 2.74-2.90 (1H, m), 3.67-3.87 (3H, m),3.89-4.05 (3H, m), 6.81-6.94 (3H, m).

Example 17 ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of 3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidinehydrochloride (340 mg), 3-ethoxy-3-oxopropanoic acid (162 mg) and DMF (8mL) were added HATU (639 mg) and N,N-diisopropylethylamine (578 mg) at0° C., and the mixture was stirred at room temperature overnight. Thereaction mixture was diluted with water and extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (150 mg).

MS: [M+H]⁺ 378.3.

Example 183-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid

To a mixture of ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate(150 mg), methanol (3 mL) and water (2 mL) was added lithium hydroxidemonohydrate (67 mg) at 0° C., and the mixture was stirred at roomtemperature for 3 hr. Methanol was removed under reduced pressure, andthe obtained aqueous solution was cooled to 0° C., acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was washed with n-pentane to give thetitle compound (100 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.51-1.55 (2H, m), 1.61-1.84 (5H, m),1.87-1.95 (2H, m), 2.01-2.12 (1H, m), 2.60-2.73 (1H, m), 3.17-3.27 (2H,m), 3.31 (2H, s), 3.43-3.71 (3H, m), 3.90-3.99 (2H, m), 6.93-7.02 (3H,m), 12.65 (1H, brs).

Example 19 ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2-methyl-3-oxopropanoate

To a mixture of 3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidinehydrochloride (400 mg), 3-ethoxy-2-methyl-3-oxopropanoic acid (205 mg)and DMF (10 mL) were added HATU (730 mg) and N,N-diisopropylethylamine(660 mg) at 0° C., and the mixture was stirred at room temperature for10 hr. The reaction mixture was diluted with cold water and extractedwith ethyl acetate. The extract was dried over anhydrous sodium sulfateand the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (200 mg).

MS: [M+H]⁺ 392.2.

Example 203-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2-methyl-3-oxopropanoicacid

To a mixture of ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2-methyl-3-oxopropanoate(200 mg), methanol (6 mL) and water (4 mL) was added lithium hydroxidemonohydrate (128 mg) at 0° C., and the mixture was stirred at roomtemperature for 5 hr. Methanol was removed under reduced pressure, andthe obtained aqueous solution was cooled to 0° C., acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was washed with n-pentane to give thetitle compound (80 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.18 (3H, dt, J=7.0, 3.6 Hz), 1.51-1.85 (7H,m), 1.90-1.92 (2H, m), 2.01-2.12 (1H, m), 2.60-2.73 (1H, m), 3.18-3.24(1H, m), 3.35-3.39 (1H, m), 3.48-3.78 (4H, m), 3.93-3.98 (2H, m),6.93-7.02 (3H, m), 12.51 (1H, brs).

Example 21 ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2,2-dimethyl-3-oxopropanoate

To a mixture of 3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidinehydrochloride (400 mg), 3-ethoxy-2,2-dimethyl-3-oxopropanoic acid (225mg) and DMF (10 mL) were added HATU (730 mg) andN,N-diisopropylethylamine (660 mg) at 0° C., and the mixture was stirredat room temperature for 10 hr. The reaction mixture was diluted withcold water and extracted with ethyl acetate. The extract was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (220 mg).

MS: [M+H]⁺ 406.5.

Example 223-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2,2-dimethyl-3-oxopropanoicacid

To a mixture of ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)-2,2-dimethyl-3-oxopropanoate(200 mg), methanol (5 mL) and water (3 mL) was added lithium hydroxidemonohydrate (124 mg) at 0° C., and the mixture was stirred at roomtemperature overnight. Methanol was removed under reduced pressure, andthe obtained aqueous solution was cooled to 0° C., acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was washed with n-pentane to give thetitle compound (125 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.27 (6H, s), 1.52-1.74 (7H, m), 1.92-2.07(3H, m), 2.58-2.67 (1H, m), 3.17-3.25 (2H, m), 3.34-3.37 (1H, m),3.46-3.57 (2H, m), 3.81-3.97 (2H, m), 6.92-6.97 (2H, m), 6.99-7.02 (1H,m), 12.78 (1H, brs).

Example 23 ethyl1-((3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)carbonyl)cyclopropanecarboxylate

To a mixture of 3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidinehydrochloride (500 mg), 1-(ethoxycarbonyl)cyclopropanecarboxylic acid(303 mg) and DMF (10 mL) were added HATU (913 mg) andN,N-diisopropylethylamine (826 mg) at 0° C., and the mixture was stirredat room temperature for 10 hr. The reaction mixture was diluted withcold water and extracted with ethyl acetate. The extract was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (300 mg).

MS: [M+H]⁺ 404.3.

Example 241-((3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)carbonyl)cyclopropanecarboxylicacid

To a mixture of ethyl1-((3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)carbonyl)cyclopropanecarboxylate(300 mg), methanol (8 mL) and water (4 mL) was added lithium hydroxidemonohydrate (187 mg) at 0° C., and the mixture was stirred at roomtemperature for hr. Methanol was removed under reduced pressure, and theobtained aqueous solution was cooled to 0° C., acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was washed with n-pentane to give thetitle compound (125 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.14-1.25 (4H, m), 1.46-1.82 (7H, m),1.85-2.11 (3H, m), 2.61-2.78 (1H, m), 3.16-3.24 (2H, m), 3.36-3.68 (3H,m), 3.86-4.03 (2H, m), 6.93-7.02 (3H, m), 12.74 (1H, brs).

Example 25 ethyl1-((3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)carbonyl)cyclobutanecarboxylate

To a mixture of 3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidinehydrochloride (400 mg), 1-(ethoxycarbonyl)cyclobutanecarboxylic acid(242 mg) and DMF (10 mL) were added HATU (730 mg) andN,N-diisopropylethylamine (660 mg) at 0° C., and the mixture was stirredat room temperature overnight. The reaction mixture was diluted withcold water and extracted with ethyl acetate. The extract was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (250 mg).

MS: [M+H]⁺ 418.3.

Example 261-((3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)carbonyl)cyclobutanecarboxylicacid

To a mixture of ethyl1-((3-((2-cyclopentyl-4-fluorophenoxy)methyl)pyrrolidin-1-yl)carbonyl)cyclobutanecarboxylate(250 mg), methanol (6 mL) and water (4 mL) was added lithium hydroxidemonohydrate (151 mg) at 0° C., and the mixture was stirred at roomtemperature for hr. Methanol was removed under reduced pressure, and theobtained aqueous solution was cooled to 0° C., acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (methanol/dichloromethane) to give the title compound(125 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.49-1.75 (8H, m) 1.90-2.07 (4H, m),2.32-2.45 (3H, m), 2.55-2.67 (1H, m), 3.00-3.05 (1H, m), 3.12-3.24 (3H,m), 3.36-3.38 (1H, m), 3.47-3.54 (1H, m), 3.79-3.99 (2H, m), 6.91-7.01(3H, m), 12.75 (1H, brs).

Example 27 ethyl3-(3-((4-bromo-2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoateA) 4-bromo-2-cyclopentylphenol

To a mixture of 2-cyclopentylphenol (10 g) and acetonitrile (60 mL) wasadded N-bromosuccinimide (10.9 g) at 0° C., and the mixture was stirredat room temperature for 4 hr. The reaction mixture was concentratedunder reduced pressure, and the residue was suspended in hexane andfiltered. The filtrate was dried over sodium sulfate and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (9.5 g).

MS: [M+H]⁺ 239.1.

B) tert-butyl3-((4-bromo-2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl 3-((tosyloxy)methyl)pyrrolidine-1-carboxylate(3.25 g), 4-bromo-2-cyclopentylphenol (2.0 g) and DMF (20 mL) was addedpotassium phosphate (5.3 g) at 0° C., and the mixture was stirred at 80°C. for 8 hr. The reaction mixture was poured into ice water, and themixture was extracted with ethyl acetate. The extract was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (3 g).

MS: [M+H]⁺ 424.1.

C) 3-((4-bromo-2-cyclopentylphenoxy)methyl)pyrrolidine hydrochloride

To a mixture of tert-butyl3-((4-bromo-2-cyclopentylphenoxy)methyl)pyrrolidine-1-carboxylate (3-g)and 1,4-dioxane (5 mL) was added 4N hydrochloric acid-1,4-dioxane (9 mL)at 0° C., and the mixture was stirred at room temperature for 4 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was washed with n-pentane to give the title compound (1.9 g).

MS: [M−HCl+H]⁺324.2.

D) ethyl3-(3-((4-bromo-2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of 3-((4-bromo-2-cyclopentylphenoxy)methyl)pyrrolidinehydrochloride (1.9 g), 3-ethoxy-3-oxopropanoic acid (766 mg) and DMF (20mL) were added HATU (3.0 g) and N,N-diisopropylethylamine (2.72 g) at 0°C., and the mixture was stirred at room temperature for 10 hr. Thereaction mixture was poured into cold water, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (1.5 g).

MS: [M+H]⁺ 438.1.

Example 283-(3-((4-bromo-2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid

To a mixture of ethyl3-(3-((4-bromo-2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate(400 mg), methanol (8 mL) and water (4 mL) was added lithium hydroxidemonohydrate (131.2 mg) at 0° C., and the mixture was stirred at roomtemperature for 2 hr. Methanol was removed under reduced pressure, andthe obtained aqueous solution was cooled to 0° C., acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was washed with n-pentane to give thetitle compound (280 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.51-1.81 (7H, m), 1.89-1.96 (2H, m),2.01-2.12 (1H, m), 2.61-2.74 (1H, m), 3.16-3.21 (2H, m), 3.28-3.33 (3H,m), 3.45-3.59 (2H, m), 3.91-4.00 (2H, m), 6.91 (1H, d, J=8.3 Hz),7.29-7.32 (2H, m), 12.64 (1H, brs).

Example 29 ethyl3-(3-((2-cyclopentyl-4-methylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

To a mixture of ethyl3-(3-((4-bromo-2-cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate(250 mg), trimethyl boroxine (142 mg) and 1,4-dioxane (8 mL) was addedpotassium carbonate (86.6 mg) at room temperature. The mixture wasdeaerated with argon, tetrakis(triphenylphosphine)palladium(0) (66 mg)was added at room temperature, and the mixture was stirred at 100° C.for 10 hr. The reaction mixture was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (100 mg).

MS: [M+H]⁺ 374.2.

Example 303-(3-((2-cyclopentyl-4-methylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid

To a mixture of ethyl3-(3-((2-cyclopentyl-4-methylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate(170 mg), methanol (5 mL) and water (2 mL) was added lithium hydroxidemonohydrate (101 mg) at 0° C., and the mixture was stirred at roomtemperature for 5 hr. Methanol was removed under reduced pressure, andthe obtained aqueous solution was cooled to 0° C., acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was washed with n-pentane, and purified byHPLC (C18, mobile phase: water/acetonitrile (1% trifluoroaceticacid-containing system)) to give the title compound (40 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.52-1.66 (4H, m), 1.70-1.81 (3H, m),1.83-1.92 (2H, m), 2.02-2.10 (1H, m), 2.20 (3H, s), 2.59-2.72 (1H, m),3.16-3.21 (2H, m), 3.32-3.33 (2H, m), 3.45-3.57 (2H, m), 3.65-3.70 (1H,m), 3.86-3.94 (2H, m), 6.80 (1H, d, J=8.3 Hz), 6.92 (1H, dd, J=8.6, 1.7Hz), 6.98 (1H, d, J=2.0 Hz), 12.64 (1H, brs).

Example 31 ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-methylpyrrolidin-1-yl)-3-oxopropanoateA) tert-butyl3-methyl-3-((((4-methylphenyl)sulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

To a mixture of tert-butyl3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate (3 g) anddichloromethane (50 mL) were added triethylamine (4.2 g) and4-dimethylaminopyridine (340 mg) at 0° C., and the mixture was stirredat 0° C. for 10 min. 4-Methylbenzene-1-sulfonyl chloride (3.98 g) wasadded at 0° C., and the mixture was stirred at room temperature for 10hr. The reaction mixture was poured into cold water and the mixture wasextracted with dichloromethane. The extract was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (4.7 g).

¹H NMR (400 MHz, CDCl₃) δ 1.08 (3H, s), 1.43 (9H, s), 1.53-1.59 (1H, m),1.73-1.86 (1H, m), 2.45 (3H, s), 3.00-3.06 (1H, m), 3.14-3.18 (1H, m),3.28-3.38 (2H, m), 3.77-3.87 (2H, m), 7.35 (2H, d, J=8.3 Hz), 7.78 (2H,d, J=8.3 Hz).

B) tert-butyl3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-methylpyrrolidine-1-carboxylate

To a mixture of 2-cyclopentyl-4-fluorophenol (1.46 g) and DMF (25 mL)was added potassium phosphate (1.46 g) at 0° C., and the mixture wasstirred for 30 min. tert-Butyl3-methyl-3-((((4-methylphenyl)sulfonyl)oxy)methyl)pyrrolidine-1-carboxylate(2.5 g) was added at 0° C., and the mixture was stirred at roomtemperature for 10 hr. The reaction mixture was poured into ice-cooledwater, and the mixture was extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.2g).

MS: [M+H]⁺ 378.2.

C) 3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-methylpyrrolidinehydrochloride

To a mixture of tert-butyl3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-methylpyrrolidine-1-carboxylate(1.2 g) and dioxane (5 mL) was added 4N hydrochloric acid-1,4-dioxane (5mL) at 0° C., and the mixture was stirred at room temperature for 2 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was washed with n-pentane to give the title compound (990 mg).

MS: [M−HCl+H]⁺ 278.2.

D) ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-methylpyrrolidin-1-yl)-3-oxopropanoate

To a mixture of3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-methylpyrrolidinehydrochloride (400 mg), 3-ethoxy-3-oxopropanoic acid (202 mg) and DMF (8mL) were added HATU (776 mg) and N,N-diisopropylethylamine (659 mg) at0° C., and the mixture was stirred at room temperature for 10 hr. Thereaction mixture was poured into cold water, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The residue was purified by silica-gel column chromatography (ethylacetate/hexane) to give the title compound (359 mg).

MS: [M+H]⁺ 392.2.

Example 323-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-methylpyrrolidin-1-yl)-3-oxopropanoicacid

To a mixture of ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-methylpyrrolidin-1-yl)-3-oxopropanoate(350 mg), methanol (8 mL) and water (4 mL) was added lithium hydroxidemonohydrate (107 mg) at 0° C., and the mixture was stirred at roomtemperature for 5 hr. Methanol was removed under reduced pressure, andthe obtained aqueous solution was cooled to 0° C., acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was washed with n-pentane, and purified byHPLC (C18, mobile phase: water/acetonitrile (0.1% HCO₂H-containingsystem)) to give the title compound (95 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.17-1.19 (3H, m), 1.52-1.79 (7H, m),1.90-1.98 (3H, m), 3.15-3.29 (2H, m), 3.33-3.39 (2H, m), 3.39-3.50 (2H,m), 3.57 (1H, t, J=7.3 Hz), 3.79-3.82 (2H, m), 6.92-6.97 (2H, m),6.99-7.02 (1H, m), 12.65 (1H, brs).

Example 33 ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-fluoropyrrolidin-1-yl)-3-oxopropanoateA) tert-butyl 3-methylenepyrrolidine-1-carboxylate

To a mixture of methyltriphenylphosphonium bromide (23.1 g) and THF (80mL) was added potassium tert-butoxide (9.0 g) at 0° C., and the mixturewas stirred at 0° C. for 30 min. tert-Butyl3-oxopyrrolidine-1-carboxylate (10 g) was added at 0° C., and themixture was stirred at room temperature for 2 hr. The reaction mixturewas poured into cold water, and the mixture was extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (6.73 g).

¹H NMR (300 MHz, CDCl₃) δ 1.46 (9H, s), 2.55 (2H, t, J=6.9 Hz),3.42-3.47 (2H, m), 3.92 (2H, brs), 4.96-4.98 (2H, m).

B) tert-butyl 1-oxa-5-azaspiro[2.4]heptane-5-carboxylate

To a mixture of m-chloroperbenzoic acid (8.1 g) and dichloromethane (50mL) was slowly added tert-butyl 3-methylenepyrrolidine-1-carboxylate(6.7 g) at 0° C., and the mixture was stirred at room temperature for 3hr. The reaction mixture was quenched with aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (2.9g).

¹H NMR (300 MHz, CDCl₃) δ 1.46 (9H, s), 1.80-1.89 (1H, m), 2.26 (1H, dt,J=13.5, 8.8 Hz), 2.93 (2H, s), 3.27 (1H, d, J=12.1 Hz), 3.59-3.62 (3H,m).

C) tert-butyl3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-hydroxypyrrolidine-1-carboxylate

To a mixture of 2-cyclopentyl-4-fluorophenol (3.1 g) and DMF (20 mL)were added potassium carbonate (6.4 g) and tert-butyl1-oxa-5-azaspiro[2.4]heptane-5-carboxylate (2.9 g) at 0° C., and themixture was stirred at 80° C. for 6 hr. The reaction mixture was pouredinto ice-cooled water, and the mixture was extracted with ethyl acetate.The extract was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (2.2 g).

MS: [M+H]⁺ 380.2.

D) tert-butyl3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-fluoropyrrolidin-1-carboxylate

To a mixture of tert-butyl3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-hydroxypyrrolidine-1-carboxylate(2.25 g) and dichloromethane (25 mL) was added diethylaminosulfurtrifluoride (1.3 g) at −78° C., and the mixture was stirred at 0° C. for2 hr. The reaction mixture was quenched with aqueous ammonium chloridesolution and extracted with dichloromethane. The extract was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (1.6 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.41 (9H, s), 1.46-1.64 (4H, m), 1.69-1.79(2H, m), 1.89-1.99 (2H, m), 2.10-2.21 (2H, m), 3.20-3.29 (1H, m),3.38-3.41 (1H, m), 3.51-3.62 (2H, m), 4.02-4.13 (1H, m), 4.20-4.30 (2H,m), 6.92-7.05 (3H, m).

E) 3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-fluoropyrrolidinhydrochloride

To a mixture of tert-butyl3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-fluoropyrrolidin-1-carboxylate(1.6 g) and 1,4-dioxane (5 mL) was added 4N hydrochloricacid-1,4-dioxane (15 mL) at 0° C., and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was concentrated underreduced pressure, and the residue was washed with n-pentane to give thetitle compound (1.0 g).

MS: [M−HCl+H]⁺ 282.1.

F) ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-fluoropyrrolidin-1-yl)-3-oxopropanoate

To a mixture of3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-fluoropyrrolidinhydrochloride (600 mg), 3-ethoxy-3-oxopropanoic acid (320 mg) and DMF(10 mL) were added HATU (1.28 g) and N,N-diisopropylethylamine (1.1 g)at 0° C., and the mixture was stirred at room temperature for 10 hr. Thereaction mixture was poured into cold water, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (520 mg).

MS: [M+H]⁺ 396.1.

Example 343-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-fluoropyrrolidin-1-yl)-3-oxopropanoicacid

To a mixture of ethyl3-(3-((2-cyclopentyl-4-fluorophenoxy)methyl)-3-fluoropyrrolidin-1-yl)-3-oxopropanoate(250 mg), methanol (5 mL) and water (2 mL) was added lithium hydroxidemonohydrate (159 mg) at 0° C., and the mixture was stirred at roomtemperature for 2 hr. Methanol was removed under reduced pressure, andthe obtained aqueous solution was cooled to 0° C., acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was washed with n-pentane, and purified byHPLC (C18, mobile phase: water/acetonitrile (1% HCO₂H-containingsystem)) to give the title compound (25 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.54-1.73 (6H, m), 1.89-2.01 (2H, m),2.15-2.35 (2H, m), 3.13-3.17 (3H, m), 3.54-4.03 (4H, m), 4.25-4.30 (2H,m), 6.96-7.02 (3H, m).

According to the methods shown in the above-mentioned Examples or amethod analogous thereto, the Example compounds in the following Tableswere produced. The Example compounds are shown in the following Tables.In the Tables, MS shows measured values.

TABLE 1-1 Ex. structural No. IUPAC name formula salt MS  13-oxo-3-((3S)-3-((2-(1- (trifluoromethyl)cyclopropyl)-phenoxy)methyl)pyrrolidin-1- yl)propanoic acid

372.2  2 3-((3S)-3-((2-(1-methylcyclo- propyl)phenoxy)methyl)pyrroli-din-1-yl)-3-oxopropanoic acid

318.0  3 3-((3S)-3-((2-cyclobutyl- phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoic acid

318.1  4 3-((3S)-3-((2-cyclopentyl- phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoic acid

332.3  5 3-((3S)-3-((2-cyclohexyl- phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoic acid

346.1  6 3-((3R)-3-((2-cyclopentyl- phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoic acid

332.3  7 3-(3-((2-cyclopentyl- phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoic acid

332.3  8 ethyl 3-oxo-3-((3S)-3-((2-(1- (trifluoromethyl)cyclopropyl)-phenoxy)methyl)pyrrolidin-1- yl)propanoate

400.3  9 ethyl 3-((3S)-3-((2-(1- methylcyclopropyl)phenoxy)-methyl)pyrrolidin-1-yl)-3- oxopropanoate

346.2 10 ethyl 3-((3S)-3-((2-cyclobutyl-phenoxy)methyl)pyrrolidin-1-yl)- 3-oxopropanoate

346.2

TABLE 1-2 Ex. structural No. IUPAC name formula salt MS 11 ethyl3-(3S)-3-((2- cyclopentylphenoxy)methyl)-pyrrolidin-1-yl)-3-oxopropanoate

360.2 12 ethyl 3-((3S)-3-((2- cyclohexylphenoxy)methyl)-pyrrolidin-1-yl)-3-oxopropanoate

374.2 13 ethyl 3-((3R)-3-((2- cyclopentylphenoxy)methyl)-pyrrolidin-1-yl)-3-oxopropanoate

360.1 14 ethyl 3-(3-((2-cyclopentyl- phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

360.1 15 methyl 3-(3-((2-cyclopentyl-4- fluorophenoxy)methyl)pyrrolidin-1-yl)-2,2-difluoro-3- oxopropanoate

400.3 16 3-(3-((2-cyclopentyl-4- fluorophenoxy)methyl)pyrrolidin-1-yl)-2,2-difluoro-3- oxopropanoic acid

384.0 17 ethyl 3-(3-((2-cyclopentyl-4- fluorophenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

378.3 18 3-(3-((2-cyclopentyl-4- fluorophenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoic acid

350.1 19 ethyl 3-(3-((2-cyclopentyl-4- fluorophenoxy)methyl)pyrrolidin-1-yl)-2-methyl-3-oxopropanoate

392.2 20 3-(3-((2-cyclopentyl-4-fluoro- phenoxy)methyl)pyrrolidin-1-yl)-2-methyl-3-oxopropanoic acid

364.2

TABLE 1-3 Ex. structural No. IUPAC name formula salt MS 21 ethyl3-(3-((2-cyclopentyl-4- fluorophenoxy)methyl)pyrrolidin-1-yl)-2,2-dimethyl-3- oxopropanoate

406.5 22 3-(3-((2-cyclopentyl-4- fluorophenoxy)methyl)pyrrolidin-1-yl)-2,2-dimethyl-3- oxopropanoic acid

378.2 23 ethyl 1-((3-((2-cyclopentyl-4- fluorophenoxy)methyl)pyrrolidin-1-yl)carbonyl)- cyclopropanecarboxylate

404.3 24 1-((3-((2-cyclopentyl-4- fluorophenoxy)methyl)pyrrolidin-1-yl)carbonyl)- cyclopropanecarboxylic acid

374.1 25 ethyl 1-((3-((2-cyclopentyl-4- fluorophenoxy)methyl)pyrrolidin-1-yl)carbonyl)- cyclobutanecarboxylate

418.3 26 1-((3-((2-cyclopentyl-4- fluorophenoxy)methyl)pyrrolidin-1-yl)carbonyl)- cyclobutanecarboxylic acid

390.2 27 ethyl 3-(3-((4-bromo-2- cyclopentylphenoxy)methyl)-pyrrolidin-1-yl)-3-oxopropanoate

438.1 28 3-(3-((4-bromo-2- cyclopentylphenoxy)methyl)-pyrrolidin-1-yl)-3-oxopropanoic acid

410.0 29 ethyl 3-(3-((2-cyclopentyl-4- methylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoate

374.2 30 3-(3-((2-cyclopentyl-4- methylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoic acid

346.2

TABLE 1-4 Ex. structural No. IUPAC name formula salt MS 31 ethyl3-(3-((2-cyclopentyl-4- fluorophenoxy)methyl)-3-methylpyrrolidin-1-yl)-3- oxopropanoate

392.2 32 3-(3-((2-cyclopentyl-4- fluorophenoxy)methyl)-3-methylpyrrolidin-1-yl)-3- oxopropanoic acid

364.2 33 ethyl 3-(3-((2-cyclopentyl-4- fluorophenoxy)methyl)-3-fluoropyrrolidin-1-yl)-3- oxopropanoate

396.1 34 3-(3-((2-cyclopentyl-4- fluorophenoxy)methyl)-3-fluoropyrrolidin-1-yl)-3- oxopropanoic acid

368.1

Experimental Example 1

Using the Retinol-RBP4-TTR ELISA system shown below, the action of thecompound of the present invention to inhibit the binding of RBP4 andretinol and TTR was evaluated.

1A: Cloning of Human RBP4 Gene and Human TTR Gene

Human RBP4 gene was cloned by PCR using human Universal cDNA (Clontech,QUICK-Clone cDNA) as a template, and the following primer sets.

RBPU: (SEQ ID NO: 1) 5′-ATATGGATCCACCATGAAGTGGGTGTGGGCGCTC-3′ RBPL:(SEQ ID NO: 2) 5′-ATATGCGGCCGCCTACAAAAGGTTTCTTTCTGATCTGC-3′

PCR reaction was performed according to the protocol attached toPyrobest polymerase (TAKARA BIO INC., LTD.). The obtained PCR productwas subjected to agarose gel (1%) electrophoresis, an about 0.6 kb DNAfragment containing RBP4 gene was recovered from the gel, digested withrestriction enzymes BamHI and NotI. DNA fragment after the restrictionenzyme treatment was subjected to agarose gel (1%) electrophoresis, anabout 0.6 kb DNA fragment was recovered, and ligated to plasmidpcDNA3.1(+) (Invitrogen) digested with restriction enzymes BamHI andNotI to give an expression plasmid pcDNA3.1(+)/hRBP4. The DNA sequenceof the inserted fragment was confirmed to have matched with the objectsequence.

Human TTR gene was cloned by PCR reaction using human small intestinecDNA (Clontech, QUICK-Clone cDNA) as a template, and the followingprimer sets.

TTRU: (SEQ ID NO: 3) 5′-ATATGGATCCACCATGGCTTCTCATCGTCTGCTCC-3′ TTRL:(SEQ ID NO: 4) 5′-ATATGCGGCCGCTCATTCCTTGGGATTGGTGACGA-3′

PCR reaction was performed according to the protocol attached toPyrobest polymerase (TAKARA BIO INC., LTD.). The obtained PCR productwas subjected to agarose gel (1%) electrophoresis, a 0.5 kb DNA fragmentcontaining TTR gene was recovered from the gel, digested withrestriction enzymes BamHI and NotI. DNA fragment after the restrictionenzyme treatment was subjected to agarose gel (1%) electrophoresis, anabout 0.5 kb DNA fragment was recovered, and ligated to plasmidpcDNA3.1(+) (Invitrogen) digested with restriction enzymes BamHI andNotI to give an expression plasmid pcDNA3.1(+)/hTTR. The DNA sequence ofthe inserted fragment was confirmed to have matched with the objectsequence.

1B: Construction of Human RBP4-his Expression Plasmid

EcoRI site was introduced into the 3′-end of hRBP4 gene by PCR using theexpression plasmid pcDNA3.1(+)/hRBP4 prepared in the above-mentioned 1Aas a template and the following primer sets.

CMVP: (SEQ ID NO: 5) 5′-TGGGAGGTCTATATAAGCAGAGCTCG-3′ RBPECO:(SEQ ID NO: 6) 5′-ATATGAATTCTTCCTTGGGATTGGTGAC-3′

PCR was performed according to the protocol attached to Z-Taq polymerase(TAKARA BIO INC., LTD.). The obtained PCR product was purified byQIAquick PCR purification Kit (QIAGEN), and digested with restrictionenzymes BamHI and EcoRI. DNA fragment after the restriction enzymetreatment was subjected to agarose gel (1%) electrophoresis, theobtained about 0.6 kb DNA fragment was recovered, and ligated to plasmidpcDNA3.1(+) (Invitrogen) digested with restriction enzymes BamHI andEcoRI to give pcDNA3.1(+)/hRBP4-Eco having EcoRI site at the 3′-end ofhRBP4 gene.

EcoRI site was introduced into the 3′-end of hTTR gene by PCR using theexpression plasmid pcDNA3.1(+)/hTTR prepared in the above-mentioned 1Aas a template and CMVP and TTRECO primer sets.

TTRECO: (SEQ ID NO: 7) 5′-ATATGAATTCCAAAAGGTTTCTTTCTGATC-3′

PCR reaction was performed according to the protocol attached to Z-Taqpolymerase (TAKARA BIO INC., LTD.). The obtained PCR product waspurified by QIAquick PCR purification Kit (QIAGEN), and digested withrestriction enzymes BamHI and EcoRI. DNA fragment after the restrictionenzyme treatment was subjected to agarose gel (1%) electrophoresis, theobtained about 0.6 kb DNA fragment was recovered, and ligated to plasmidpcDNA3.1(+) (Invitrogen) digested with restriction enzymes BamHI andEcoRI to give pcDNA3.1(+)/hTTR-Eco having EcoRI site at the 3′-end ofhTTR gene.

TTR-His expression plasmid pcDNA3.1(+)/hTTR-His wherein His tag is addedto the C-terminal of human TTR was prepared by inserting a synthetic DNAfragment containing His tag sequence prepared by annealing the followingoligoDNA into the EcoRI site and NotI site of pcDNA3.1(+)/hTTR-Ecoprepared as mentioned above.

HISENU: (SEQ ID NO: 8) 5′-AATTCCATCATCATCATCATCACTAGGC-3′ HISENL:(SEQ ID NO: 9) 5′-GGCCGCCTAGTGATGATGATGATGATGG-3′

HISENU and HISENL were each dissolved at a concentration of 25 pmole/uL,heated at 94° C. for 5 min, cooled to room temperature to allow forannealing, whereby synthetic DNA fragment containing His tag sequencewas obtained. pcDNA3.1(+)/hTTR-Eco was digested with EcoRI and NotI, theDNA fragment after the restriction enzyme treatment was subjected toagarose gel (1%) electrophoresis, the obtained about 5.9 kb DNA fragmentwas recovered, and a synthetic DNA fragment containing His tag sequencewas ligated thereto to give TTR-His expression plasmidpcDNA3.1(+)/hTTR-His wherein His tag is added to the C-terminal of humanTTR.

RBP4-His expression plasmid pcDNA3.1(+)/hRBP4-His wherein His tag isadded to the C-terminal of human RBP4 was prepared as follows.pcDNA3.1(+)/hRBP4-Eco was digested with restriction enzymes EcoRI andDraIII, subjected to agarose gel (1%) electrophoresis, and the obtainedabout 6.0 kb DNA fragment was recovered. pcDNA3.1(+)/hTTR-His wasdigested with restriction enzymes EcoRI and DraIII, subjected to agarosegel (1%) electrophoresis, and the obtained about 6.0 kb DNA fragment wasrecovered. The both fragments were ligated to give RBP4-His expressionplasmid pcDNA3.1(+)/hRBP4-His wherein His tag is added to the C-terminalof human RBP4.

1C: Preparation of Human RBP4-his

Human RBP4-His was expressed using FreeStyle 293 expression system(Invitrogen) and expression plasmid pcDNA3.1(+)/hRBP4-His prepared inthe above-mentioned 1B. According to the protocol attached to theFreeStyle 293 expression system, 600 mL of culture medium was used forexpression. After transfection and 3 days of culture, the culturesupernatant containing secreted hRBP4-His was recovered. The culturesupernatant was repeatedly concentrated using VIVACELL 250 (molecularweight cutoff 10K, VIVASCIENCE), and diluted with 20 mM Tris (pH 8),whereby the buffer was substituted. The liquid was adsorbed by passagethrough TOYOPEARL DEAE-650 M column (1 cm ID×10 cm, Tosoh Corporation)equilibrated with 20 mM Tris buffer (pH 8) at a flow rate of 2.5 mL/min,and eluted at 0 to 0.35 M NaCl gradient to give human RBP4-Hisfractions. These fractions were concentrated to about 5 mL usingVivaspin 20 (molecular weight cutoff 10K, VIVASCIENCE). The Concentratedsolution was passed through HiLoad 26/60 Superdex 200 pg column (2.6 cmID×60 cm, GE Healthcare) equilibrated with TBS (pH 7.4), and eluted withTBS (pH 7.4). The fraction containing human RBP4-His was recovered, andconcentrated to about 8 mL using Vivaspin 20 (molecular weight cutoff10K, VIVASCIENCE). About 8 mg of human RBP4-His was obtained from 600 mLof the culture medium.

1D: Preparation of Human TTR

Human TTR was expressed using FreeStyle 293 expression system(Invitrogen) and expression plasmid pcDNA3.1(+)/hTTR prepared in theabove-mentioned 1A. According to the protocol attached to the FreeStyle293 expression system, 600 mL of culture medium was used for expression.After transfection and 3 days of culture, the culture supernatantcontaining secreted human TTR was recovered. The culture supernatant wasrepeatedly concentrated using VIVACELL 250 (molecular weight cutoff 10K,VIVASCIENCE), and diluted with 20 mM Tris (pH 8), whereby the buffer wassubstituted. The liquid was adsorbed by passage through TOYOPEARLDEAE-650 M column (1 cm ID×10 cm, Tosoh Corporation) equilibrated with20 mM Tris buffer (pH 8) at a flow rate of 2.5 mL/min, and eluted at 0to 0.55 M NaCl gradient to give human TTR fractions. These fractionswere repeatedly concentrated using Vivaspin 20 (molecular weight cutoff10K, VIVASCIENCE), and diluted with 20 mM Tris (pH 8), whereby thebuffer was substituted. The liquid was adsorbed by passage throughHiLoad Q Sepharose HP column (1.6 cm ID×100 cm, GE Healthcare)equilibrated with 20 mM Tris buffer (pH 8) at a flow rate of 1.0 mL/min,and eluted at 0 to 0.4 M NaCl gradient to give human TTR fractions.These fractions were concentrated to about 5 mL using Vivaspin 20(molecular weight cutoff 10K, VIVASCIENCE). The Concentrated solutionwas passed through HiLoad 26/60 Superdex 75 pg column (2.6 cm ID×60 cm,GE Healthcare) equilibrated with PBS (pH 7.4), and eluted with TBS (pH7.4). The fraction containing human TTR was recovered, and concentratedto about 5 mL using Vivaspin 20 (molecular weight cutoff 10K,VIVASCIENCE). About 6 mg of human TTR was obtained from 600 mL of theculture medium.

1E: Preparation of Human TTR-Biotin

Human TTR prepared in the above-mentioned 1D was labeled with biotinusing Biotinylation Kit (Sulfo-Osu) (DOJINDO LABORATORIES) according tothe attached protocol to prepare human TTR-biotin. Human TTR (5.0 mg)was repeatedly concentrated using Vivaspin 6 (molecular weight cutoff10K, VIVASCIENCE) and diluted with 50 mM NaHCO₃, whereby the buffer wassubstituted. This solution was diluted with 50 mM NaHCO₃ to set theconcentration of human TTR to 2.0 mg/mL, and aqueous Biotin-(AC5)2Sulfo-OSu solution (10 mg/mL) (9.9 uL) was added and the mixture wasreacted at 25° C. for 2 hr. The solution after the reaction was passedthrough NAP-25 column (GE Healthcare) equilibrated with PBS (pH 7.4),eluted with PBS (pH 7.4) and an eluate (3.5 mL) containing humanTTR-biotin was recovered.

1F: Binding Assay by Retinol-RBP4-TTR ELISA

This ELISA system detects a complex with RBP4 and TTR based on theretinol dependent binding of RBP4 to TTR.

The His-tagged human RBP4 used was prepared in the above-mentioned 1C.

The biotinylated human TTR used was prepared in the above-mentioned 1E.

Streptavidin (20 μl) (10 μg/ml Streptavidin type II (Wako Pure ChemicalIndustries, Ltd.), 10 mM Tris-HCl (pH 7.5), 10 mM NaCl) was added to a384 well blackplate (Nunc MaxiSorp, Thermo Fisher Scientific Inc.), andthe plate was centrifuged (1000 rpm, 1 min) and coated at 4° C.overnight. The plate was washed twice with PBST (PBS, 0.05% Tween 20,100 μl/well), and blocked with 25% Block Ace (Snow Brand Milk ProductsCo., Ltd., PBS, 100 μl/well). The plate was subjected to centrifugation(1000 rpm, 1 min), and incubated at room temperature for 4 hr or 4° C.overnight. The plate was washed twice with PBST (PBS, 0.05% Tween 20,100 μl/well), and biotinylated human TTR (stock solution concentration1.0 mg/ml) diluted 750-fold with PBST was added at 20 μl/well. The platewas subjected to centrifugation (1000 rpm, 1 min), and further stood atroom temperature for 1.5 hr or 4° C. overnight. The plate was washed 3times with PBST (100 μl/well), and His-tagged human RBP4 (stock solutionconcentration 1.28 mg/ml) diluted 4000-fold with a reaction buffer (50mM Tris-HCl, 150 mM NaCl, 0.005% Tween 20, 1 mM DTT, 0.1% BSA) was addedat 10 μl/well. The dilution of the compound (200-fold concentration) wasprepared with DMSO, and 1.6 μl each was added to a reaction buffer (320μl) containing retinol (50 nM) (Sigma-Aldrich Co.). A reaction buffer(320 μl) containing retinol and added with DMSO was used as a positivecontrol, and a reaction buffer (320 μl) not containing retinol and addedwith DMSO was used as a negative control. A mixed solution of retinoland the compound was added to the plate at 15 μl/well. The plate wasstirred in a plate mixer, centrifuged (1000 rpm, 1 min), and reacted atroom temperature for 2 hr. Anti-His HRP-conjugated antibody (QIAGEN)solution diluted with a reaction buffer was added at μl/well,centrifuged (1000 rpm, 1 min), and reacted at room temperature for 30min. The plate was washed 3 times with PBST (100 μl/well), SuperSignalELISA Femto Maximum Sensitivity Substrate reagent (PIERCE, Thermo FisherScientific Inc.) was added at 30 μl/well, and the luminescence wasmeasured by a plate reader (Envision).

The binding inhibitory activity of the compound was determined by100×(positive control value−test compound value)/(positive controlvalue−negative control value). The results are shown in Table 2.

TABLE 2 Example human RBP4 binding inhibitory No. activity (% at 10 μM)Example 1 100 Example 2 98 Example 3 98 Example 4 100 Example 5 100Example 6 100 Example 7 100

From the above-mentioned results, it was clarified that the compound ofthe present invention inhibits the binding of RBP4, and retinol and TTR.

Experimental Example 2

The blood RBP4-lowering action of the compound of the present inventionwas evaluated using C57BL/6J mouse.

Male 7- to 10-week-old C57BL/6J mice (Japan Charles River) wereacclimation reared under free food ingestion conditions on CE-2 solidfeed (CLEA Japan, Inc.) for 4 to 6 days, and randomly grouped (4 or 5per group). On the day of the test, blood samples were collected fromthe tail vein, and plasma was separated (0 hr value). Thereafter, a testcompound (Example 1, 4, 5, 6 or 7) was orally administered at a dose of5 mg/kg (solvent: 0.5% methylcellulose solution (10 mL/kg)). At 8 hrafter the compound was administered, blood samples were collected fromthe tail vein and plasma was separated. Immediately after the bloodsamples were collected, the test compound was orally administered againat a dose of 5 mg/kg, and blood samples were collected again at 24 hrafter the initial administration. In Examples 2, 3 and 8, the initialadministration alone was performed at a dose of 10 mg/kg. The daily doseof all the test compounds was set to 10 mg/kg. A 0.5% methylcellulosesolution (10 mL/kg) was orally administered to the control group.

The amount of RBP4 in the collected plasma was measured by the ELISAmethod. Using rabbit anti-mouse RBP4 polyclonal antibody (Hokudo Co.,Ltd.), RBP4 was quantified by the following process. A 96 well ELISAplate was coated with 50 μg/mL antibody (100 μL), and stood at 4° C.overnight or at room temperature for 2 hr. After blocking with BlockAce(Dainippon Pharmaceutical Co., Ltd.), 100 μL of mouse RBP4 or sample wasadded and the plate was stood at room temperature for 2 hr, washed withPBS-0.5% Tween20, added with HRP-labeled anti-RBP4 antibody (prepared bylabeling RBP4 polyclonal antibody (Hokudo Co., Ltd.) with HRP (DOJINDOLABORATORIES)) (100 μL), and stood at room temperature for 1 hr. Afterwashing, TMB (Sigma) was added at room temperature for 20 min to allowfor color development. The reaction was quenched with 2N sulfuric acidand the absorbance at A450 nm was measured by a platereader. Variationfrom the initial value of each individual was taken as the relativevalue to the control group (initial value/control value, %) at each timepoint. The results are shown below in mean±standard deviation (n=4 or5).

TABLE 3 RBP4 (initial value/control value %) Example No. dose 8 hr later24 hr later 1 5 mg/kg 30.02 ± 6.85 28.49 ± 5.16 2 10 mg/kg  11.82 ± 3.24 36.40 ± 12.19 3 10 mg/kg  37.20 ± 3.71 95.57 ± 8.55 4 5 mg/kg 29.93 ±6.80 56.02 ± 9.72 5 5 mg/kg 32.30 ± 1.76 62.83 ± 4.70 6 5 mg/kg  41.42 ±13.96  41.90 ± 20.25 7 5 mg/kg 33.90 ± 6.60 53.72 ± 6.97 8 10 mg/kg 77.35 ± 7.08 92.76 ± 6.81

All the above-mentioned compounds showed a lower value than the controlgroup 8 hr after the administration. These results show that thecompound of the present invention has a blood RBP4-lowering action.

Experimental Example 3

The suppressive action for accumulation of retinoid metabolitebis-retinoid N-retinylidene-N-retinylethanolamine (A2E) in the eyeball,of the compound of the present invention, was evaluated usingATP-binding cassette A4 knockout (ABCA4 KO) mouse. A2E is the majorconstituent component of Lipofuscin in the eyeball, and is involved inthe onset and pathology progression in atrophic age-related maculardegeneration and Stargardt's disease. ABCA4 KO mouse was confirmed toshow remarkable accumulation of A2E, Lipofuscin along with aging, and isknown as an animal model of atrophic age-related macular degenerationand Stargardt's disease.

8-Week-old male ABCA4 KO mice were randomly grouped, and 0.5%methylcellulose solution was orally administered to the control group,and 0.5% methylcellulose suspension of a compound at a dose shown in thefollowing Table was orally administered to the test compound group, eachtwice per day at 10 mL/kg. Each group contained 6 mice. After repetitiveadministration for 12 weeks, eyeball was isolated under anesthesia.

In the eyeball, A2E was measured by the HPLC method. A2E referencestandard was synthesized from all-trans retinal, ethanolamine in aceticacid-added ethanol. First, 0.3 mL of PBS and zirconia beads were addedto the eyeball, and homogenate was prepared using Mixer Mill MM 300(QIAGEN). A chloroform:methanol (2:1) solution (0.8 mL) was added andthe mixture was stirred for 5 min. The lower layer was separately takenin a different tube, the chloroform:methanol (2:1) solution (0.6 mL) wasfurther added and the mixture was stirred for 5 min. The lower layer wascombined with one separated earlier, and dried to solidness by blowingnitrogen gas. 0.05 mL of 85% acetonitrile solution was added and themixture was stirred to give a measurement sample. For HPLC, Alliancee2695 and Photo diode array 2998 (PDA) (Waters) were used, and Empower 2was used as an analysis software. The column used was Atlantis dC18 (3μm, 3.9×150 mm) (Waters), and the column temperature was set to 40° C.As the mobile phase, a mixed solution of acetonitrile and distilledwater (containing 0.1% trifluoroacetic acid) was used at 1 mL/min and,as the gradient conditions, acetonitrile concentration was raised from85% to 100% over 15 min, and then immediately decreased to 85% and onesample was monitored for 20 min. Quantification was performed atultraviolet absorbance at 440 nm by PDA.

TABLE 4 Example No. dose A2E (% of control value) 4 5 mg/kg 53.94 ±15.16

Formulation Example 1 (Production of Capsule)

1) compound of Example 1 30 mg 2) microcrystalline cellulose 10 mg 3)lactose 19 mg 4) magnesium stearate  1 mg total 60 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (production of tablet)

1) compound of Example 1 30 g 2) lactose 50 g 3) cornstarch 15 g 4)calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g 1000tablets 140 g in total

The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water,vacuum dried and sieved. The sieved powder is mixed with 14 g of 4) and1 g of 5), and the mixture is punched by a tableting machine. In thisway, 1000 tablets containing 30 mg of the compound of Example 1 pertablet are obtained.

Formulation Example 3 (Production of Ointment)

1) compound of Example 1 0.5 g 2) liquid paraffin   1 g 3) whitepetrolatum 98.5 g  total 100 g 

1), 2) are thoroughly mixed in a mortar, 3) is gradually added withkneading to the total amount of 100 g. The obtained mixture is dividedand filled in a tube to give an ointment.

Formulation Example 4 (Production of Eye Drop)

 1) compound of Example 1 0.05 g  2) boric acid 1.2 g  3) L-sodiumglutamate 0.2 g  4) sodium edetate 0.005 g  5) dibutylhydroxytoluene0.005 g  6) chlorobutanol 0.1 g  7) benzalkonium chloride (10 w/v %)0.05 mL  8) l-menthol 0.008 g  9) macrogol 4000 0.4 g 10) sodiumhydroxide q.s. 11) sterile purified water added to 100 mL

The above-mentioned components are mixed to give an eye drop.

INDUSTRIAL APPLICABILITY

The compound of the present invention has a superior RBP4-loweringaction, and is useful as a medicament for the prophylaxis or treatmentof a disease or condition mediated by an increase in RBP4 or retinolsupplied by RBP4 such as age-related macular degeneration, Stargardt'sdisease and the like.

This application is based on patent application No. 2014-217769 filed inJapan, the contents of which are incorporated in full herein by thisreference.

SEQ ID NO: 1: PCR primer (RBPU)SEQ ID NO: 2: PCR primer (RBPL)SEQ ID NO: 3: PCR primer (TTRU)SEQ ID NO: 4: PCR primer (TTRL)SEQ ID NO: 5: PCR primer (CMVP)SEQ ID NO: 6: PCR primer (RBPECO)SEQ ID NO: 7: PCR primer (TTRECO)SEQ ID NO: 8: oligonucleotide (HISENU) for producing synthetic genesegment containing His tag sequenceSEQ ID NO: 9: oligonucleotide (HISENL) for producing synthetic genesegment containing His tag sequence

1. A compound represented by the formula (I):

wherein ring A is an optionally further substituted benzene ring; R is ahydrogen atom or a C₁₋₆ alkyl group; R¹ is a C₃₋₆ cycloalkyl groupoptionally substituted by substituent(s) selected from a fluorine atomand an optionally substituted alkyl group; ring B is an optionallyfurther substituted pyrrolidine ring; and R² and R³ are eachindependently a hydrogen atom or a substituent, or R² and R³ areoptionally joined to form an optionally substituted ring, or a saltthereof.
 2. The compound according to claim 1, wherein R is a hydrogenatom, or a salt thereof.
 3. The compound according to claim 1, whereinring A is a benzene ring optionally further substituted by a substituentselected from a halogen atom and a C₁₋₆ alkyl group, or a salt thereof.4. The compound according to claim 1, wherein R¹ is a C₃₋₆ cycloalkylgroup optionally substituted by substituent(s) selected from a C₁₋₆alkyl group optionally substituted by a fluorine atom, or a saltthereof.
 5. The compound according to claim 1, wherein ring B is apyrrolidine ring optionally further substituted by a substituentselected from a fluorine atom and a C₁₋₆ alkyl group, or a salt thereof.6. The compound according to claim 1, wherein R² and R³ are eachindependently a hydrogen atom, a halogen atom, or C₁₋₆ alkyl, or R² andR³ are optionally joined to form a C₃₋₄ cycloalkane ring, or a saltthereof.
 7. The compound according to claim 1, wherein ring A is abenzene ring optionally further substituted by a substituent selectedfrom a halogen atom and a C₁₋₆ alkyl group; R¹ is a C₃₋₆ cycloalkylgroup optionally substituted by substituent(s) selected from a C₁₋₆alkyl group optionally substituted by a fluorine atom; ring B is apyrrolidine ring optionally further substituted by a substituentselected from a fluorine atom and a C₁₋₆ alkyl group; R² and R³ are eachindependently a hydrogen atom, a halogen atom, or C₁₋₆ alkyl, or R² andR³ are optionally joined to form a C₃₋₄ cycloalkane ring, or a saltthereof. 8.3-((3S)-3-((2-(1-Methylcyclopropyl)phenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid or a salt thereof. 9.3-(3-((2-Cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoic acidor a salt thereof. 10.3-((3R)-3-((2-Cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid or a salt thereof. 11.3-((3S)-3-((2-Cyclopentylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid or a salt thereof. 12.3-((3S)-3-((2-Cyclohexylphenoxy)methyl)pyrrolidin-1-yl)-3-oxopropanoicacid or a salt thereof.
 13. A medicament comprising the compoundaccording to claim 1, or a salt thereof. 14-16. (canceled)
 17. A methodof lowering retinol binding protein 4 in a mammal, comprisingadministering an effective amount of the compound according to claim 1,or a salt thereof to the mammal.
 18. A method for the prophylaxis ortreatment of macular degeneration and/or Stargardt's disease in amammal, comprising administering an effective amount of the compoundaccording to claim 1, or a salt thereof to the mammal.
 19. (canceled)20. The compound according to claim 2, wherein ring A is a benzene ringoptionally further substituted by a substituent selected from a halogenatom and a C₁₋₆ alkyl group, or a salt thereof.
 21. The compoundaccording to claim 2, wherein R¹ is a C₃₋₆ cycloalkyl group optionallysubstituted by substituent(s) selected from a C₁₋₆ alkyl groupoptionally substituted by a fluorine atom, or a salt thereof.
 22. Thecompound according to claim 2, wherein ring B is a pyrrolidine ringoptionally further substituted by a substituent selected from a fluorineatom and a C₁₋₆ alkyl group, or a salt thereof.
 23. The compoundaccording to claim 2, wherein R² and R³ are each independently ahydrogen atom, a halogen atom, or C₁₋₆ alkyl, or R² and R³ areoptionally joined to form a C₃₋₄ cycloalkane ring, or a salt thereof.24. The compound according to claim 2, wherein ring A is a benzene ringoptionally further substituted by a substituent selected from a halogenatom and a C₁₋₆ alkyl group; R¹ is a C₃₋₆ cycloalkyl group optionallysubstituted by substituent(s) selected from a C₁₋₆ alkyl groupoptionally substituted by a fluorine atom; ring B is a pyrrolidine ringoptionally further substituted by a substituent selected from a fluorineatom and a C₁₋₆ alkyl group; R² and R³ are each independently a hydrogenatom, a halogen atom, or C₁₋₆ alkyl, or R² and R³ are optionally joinedto form a C₃₋₄ cycloalkane ring, or a salt thereof.
 25. A medicamentcomprising the compound according to claim 2, or a salt thereof.
 26. Amethod of lowering retinol binding protein 4 in a mammal, comprisingadministering an effective amount of the compound according to claim 2,or a salt thereof to the mammal.
 27. A method for the prophylaxis ortreatment of macular degeneration and/or Stargardt's disease in amammal, comprising administering an effective amount of the compoundaccording to claim 2, or a salt thereof to the mammal.